T-Lymphocytes; Vaccines; Global Health; Developmental Biology; Infectious Disease Medicine
Rheumatic Diseases Research Core
Memory T and B cells constitute our primary system of defense against reoccurring infectious disease and the ability to form these cells is the ultimate goal of vaccination. My laboratory aims to understand how memory T cells are generated during infection and vaccination, and why, in some circumstances, an immunization fails to induce long-term T cell immunity. We are also learning how T cells are regulated in tumor microenvironments to better understand how their functions become suppressed as they infiltrate tumors in order to develop new methods of immunotherapy that enhance anti-tumor responses. Using several powerful model systems of infection or cancer in mice, we are elucidating mechanisms involved in the development of protective and long-lived memory T cells that form after acute infection or conversely, of dysfunctional or “exhausted” T cells that form in tumors or during chronic viral infections. Our studies are aimed at identifying the signals and genetic pathways that regulate the differentiation of T cells in these different types of environments so that we can design new ways to optimize the formation of highly functional, protective memory T cells to fight infection and cancer.
Specialized Terms: Mechanisms of memory T cell development; Developmental Biology; Immunobiology; Immunology; Vaccine; Immunobiology; T-Cells; Vaccines; Adaptive immunity and immunological memory to viruses
Extensive Research Description
What are the decisive factors that determine which effector cells survive to become long-lived memory cells and which cells die during the contraction phase? We have characterized the transcriptome of effector and memory T cells and identified genetic pathways and several transcription factors that regulate this life or death decision in activated T cells. Our work has helped to outline a model of effector T cell differentiation wherein a small subset of T cells develop into memory precursor cells that are more fit to persist following the first infection than the majority of effector cells. These memory precursor cells develop into long-lived memory T cells that protect against re-infection. Several types of memory T cells, which differ by their phenotypes, functions and anatomical locations, are produced to create a sophisticated, multi-layered defense system. Conceptually, the memory T cells are divided into three subsets: (1) Tissue resident memory T (TRM) cells, which locally reside in mucosal tissues to provide the front line of defense against pathogens that breach our barriers; (2) Effector memory T (TEM) cells, which circulate through the blood and tissues and are rapidly recruited to the sites of inflammation upon reinfection; and (3) central memory T (TCM) cells, which circulate through the blood and lymphoid organs to produce a second wave of effector T cells upon reinfection. TCM cell populations also contain multipotent “memory stem cells" that self-renew to sustain the memory T cell population over time.
Despite this general knowledge, we lack a deep understanding of how different types of memory T cells are generated during an immune response and persist thereafter to provide protective immunity upon reinfection. Such knowledge will have a significant impact on the development of vaccines and immunotherapies to fight infectious disease, cancer, and autoimmunity. My lab has spent the last decade elucidating regulatory pathways that control whether an effector T cell lives and adopts memory cell fates or terminally differentiates into shorter-lived effector cells and dies. These discoveries have shown that memory T cell fate determination is influenced by environmental cues and a balance of inflammatory and anti-inflammatory cytokines. Currently, my lab is trying to understand how signals in the tissue microenvironment and nutrient availability governs changes in gene expression, epigenetic remodeling and memory T cell metabolism that regulate the types of memory T cells that form and their homeostasis following infection (Figure 1). Work in this area will not only reveal basic principles in the generation and maintenance of memory T cells, but will also enhance our understanding of broad biological principles in tissue and tissue stem cell homeostasis, tumor microenvironments, and control of cellular metabolism by environmental conditions. Currently, we are focusing on several fundamental questions surrounding the development of protective memory T cells to fight infectious disease and cancer.
First, little is known about how tissues specify memory T cell properties and regulate their long-term survival and homeostasis. To develop a multilayered defense system, TCM, TEM and TRM cells must distribute themselves broadly and adopt tissue-specific properties dictated by their environments. We do not understand even basic aspects of how this occurs: for example, what are the relevant tissue-trophic factors and cell types that govern this? We are trying to elucidate the key components of the tissue microenvironment that direct transcriptional and epigenetic changes in memory T cells as they undergo environmental adaptation to different tissues and inflammatory conditions. This work is paramount to developing vaccines with tissue-targeting precision that protect against different routes of pathogen entry (e.g., airways, skin, genitals, and blood).
A second major gap exists in our understanding of the metabolic determinants of memory T cell longevity and self-renewal. We know very little about the metabolic and nutrient-utilization pathways that regulate survival and self-renewal of the different memory T cell subsets in various tissues. One recent breakthrough is our discovery that triglyceride storage is essential for the longevity and self-renewal of memory T cells. We are studying how lipid synthesis and storage are regulated in memory T cells by T cell growth factors and tissue environments. In addition to the relevance to T cell biology, this work will likely reveal conserved paradigms for metabolic control of stem cell longevity and self-renewal in general.
Third, our understanding of the functional and metabolic connections between T cells and tumors is in its infancy. Central goals of our work are to understand how T cells are regulated by the tumor microenvironment and determine if the metabolic rate of the tumor itself modulates that of the infiltrating T cells. We are also addressing the novel concept that nutrient competition between the T cells and tumor cells is a key component of immunosuppression in the tumor microenvironment. We will also examine an unexplored process of tumor “metabolic editing”, to determine if T cell immunosurveillance actually selects for cancer cells with higher metabolic rates and intensifies nutrient competition, paradoxically promoting tumor progression.
Memory CD8 T cell differentiation
Memory CD4 T cell differentiation
Chronic viral infection
Tumor Immunology and Immunotherapy
FoxO1 directly regulates the expression of PD-1 and sustains viral specific CD8+ T-cell responses during chronic infection.
Staron M, Gray S, Li MO, Ip WK, Kaech SM. FoxO1 directly regulates the expression of PD-1 and sustains viral specific CD8+ T-cell responses during chronic infection. Immunity 41(5) 802-14 (2014). PMCID in Progress
CD4 T cells required for development and function of tissue resident memory CD8 T cells through a T-bet-dependent mechanism.
Laidlaw BJ, Zhang N, Craft J, Kaech SM. CD4 T cells required for development and function of tissue resident memory CD8 T cells through a T-bet-dependent mechanism. Immunity 41(4):633-45 (2014). PMCID in Progress.
Immune-based antitumor effects of BRAF inhibitors rely on signaling by CD40L and IFNγ.
Ho PC, Meeth KM, Tsui YC, Srivastava B, Bosenberg MW, Kaech SM. Immune-based antitumor effects of BRAF Inhibitors rely on signaling by CD40L and IFN-?. Cancer Res, 74(12):3205-17 (2014). PMCID: PMC4063281.
TLR4 ligands LPS and MPLA differentially regulate effector and memory CD8+ T cell differentiation.
Cui W, Joshi NS, Liu Y, Meng H, Kleinstein SH and Kaech SM. TLR4 ligands LPS and MPLA differentially regulate effector and memory CD8+ T cell differentiation. J Immunol, 92(9):4221-32 (2014). PMCID: PMC4071140.
Transcription Factor STAT3 and Type I Interferons Are Corepressive Insulators for Differentiation of Follicular Helper and T Helper 1 Cells.
Ray JP, Marshall HD, Laidlaw BJ, Staron MM, Kaech SM, Craft J. Transcription Factor STAT3 and Type I Interferons Are Corepressive Insulators for Differentiation of Follicular Helper and T Helper 1 Cells. Immunity 40(3):367-77 (2014). PMCID: PMC3992517.
- Parish, IA, Marshall HD, Staron M, Lang PA, Brüstle A, Chen JH, Cui W, Ohashi PS, Weaver CT and Kaech SM. Blimp-1 triggers the formation of immunoregulatory IL-10 producing Th1 cells during chronic viral infection. J Clin Invest, 124(8):3455-68 (2014). PMCID: PMC4109559.
Role of sustained antigen release from nanoparticle vaccines in shaping the T cell memory phenotype.
Demento SL, Cui W, Criscione JM, Stern E, Tulipan J, Kaech SM, Fahmy TM. Role of sustained antigen release from nanoparticle vaccines in shaping the T cell memory phenotype. Biomaterials. 19:4957-64 (2012). PMID:224840449. PMCID in Progress.
An IL-21/IL-10/STAT3 pathway is critical for functional maturation of memory CD8+ T cells.
Cui W, Liu Y, Weinstein JS, Craft J & Kaech SM. An IL-21/IL-10/STAT3 pathway is critical for functional maturation of memory CD8+ T cells. Immunity 35:792-805 (2011). PMCID in progress.
Differential Expression of Ly6C and T-bet Distinguish Effector and Memory Th1 CD4(+) Cell Properties during Viral Infection.
Marshall HD, Chandele A, Jung YW, Meng H, Poholek AC, Parish IA, Rustishauser R, Cui W, Kleinstein SH, Craft J and Kaech SM. Differential Expression of Ly6C and T-bet Distinguish Effector and Memory Th1 CD4(+) Cell Properties during Viral Infection. Immunity 35:633-46 (2011). PMCID in process.
Increased numbers of pre-existing memory CD8 T cells and decreased T-bet expression can restrain terminal differentiation of secondary effector and memory CD8 T cells.
Joshi NS, Cui W, Dominguez CX, Chen JH, Hand TW and Kaech SM. Increased numbers of pre-existing memory CD8 T cells and decreased T-bet expression can restrain terminal differentiation of secondary effector and memory CD8 T cells. J Immunol 187(8):4068-76 (2011). PMCID in process.
Differential localization of effector and memory CD8 T cell subsets in lymphoid organs during acute viral infection.
Jung YW, Rutishauser R, Nikhil JS, Haberman AM and Kaech SM. Differential localization of effector and memory CD8 T cell subsets in lymphoid organs during acute viral infection. J Immunol 185:5315-25 (2010). PMCID in progress.
Differential effects of STAT5 and P13K/AKT signaling on effector and memory CD8 T cell survival.
Hand TW, Jung YW, Cui W, Sefik E, Liu Y, Joshi NS, Chandele A and Kaech SM. Differential effects of STAT5 and P13K/AKT signaling on effector and memory CD8 T cell survival. PNAS 107:16601-6 (2010). PMCID: PMC2944719.
In vivo regulation of Bcl6 and T follicular helper cell development.
Poholek AC, Hansen K, Hernandez SG, Eto D, Chandele A, Dong, X, Odegard JM, Kaech SM, Dent AL, Crotty S and Craft J. Bcl6 regulation and TFH cell development. J Immunol 185:313-26 (2010). PMCID: PMC2891136.
Blimp-1 is Required for the Terminal Differentiation of Virus-Specific Effector and Memory CD8 T cells.
Rutishauser RL, Martins GA, Kalachikov S, Chandele A, Parish IA, Jacob J, Calame K, Kaech SM. Blimp-1 is Required for the Terminal Differentiation of Virus-Specific Effector and Memory CD8 T cells. Immunity 31: 296-308 (2009).
Effects of Signal 3 during CD8 T cell priming: Bystander Production of IL-12 enhances effector T cell expansion but promotes terminal differentiation.
Cui W, Joshi NS, Jiang A, Whitmire JK, Whitton JL, Kaech SM. Vaccine. 2009 Mar 26;27(15):2177-87. doi: 10.1016/j.vaccine.2009.01.088. Epub 2009 Feb 6.
Formation of IL-7Rahi and IL-7Ralo CD8 T Cells during Infection is Regulated by the Opposing Functions of GABPa and Gfi-1.
Chandele A, Joshi NS, Zhu J, Paul WE, Leonard WJ, Kaech SM. Formation of IL-7Rahi and IL-7Ralo CD8 T Cells during Infection is Regulated by the Opposing Functions of GABPa and Gfi-1. J Immunol 8: 5309-19 (2008). PMID: 18390712.
Inflammation Directs Memory Precursor and Short-Lived Effector CD8+ T Cell Fates via the Graded Expression of T-Bet Transcription Factor.
Joshi NS, Cui W, Chandele A, Heung K-L, Urso D, Hagman J, Gapin L, Kaech SM. Immunity. 2007 Aug;27(2):281-95.
Heterogeneity and Cell Fate Decisions in Effector and Memory CD8+ T Cell Differentiation During Viral Infection.
Kaech SM and Wherry EJ. Heterogeneity and Cell Fate Decisions in Effector and Memory CD8+ T Cell Differentiation During Viral Infection. Immunity 27:393-405 (2007). PMID: 17892848.
Expression of IL-7 receptor alpha is necessary but not sufficient for the formation of memory CD8 T cells during viral infection.
Hand T, Morre M, Kaech SM. Expression of Interleukin-7 Receptor a Is Necessary but not Sufficient for the Formation of Memory CD8 T Cells During Viral Infection. PNAS 104: 11730-11735 (2007). PMID: 17609371.
Selective expression of the IL-7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells.
Kaech, S.M., Tan, J.T., Wherry, E.J., Konieczny, B.T., Surh, C.D., and Ahmed, R. (2003). Selective expression of the IL-7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nature Immunol. 4:1191-98.
Production of IL-10 by CD4(+) regulatory T cells during the resolution of infection promotes the maturation of memory CD8(+) T cells.
Laidlaw BJ, Cui W, Amezquita RA, Gray SM, Guan T, Lu Y, Kobayashi Y, Flavell RA, Kleinstein SH, Craft J, Kaech SM. Nat Immunol. 2015 Aug;16(8):871-9.
Full List of PubMed Publications
- Guan T, Dominguez CX, Amezquita RA, Laidlaw BJ, Cheng J, Henao-Mejia J, Williams A, Flavell RA, Lu J, Kaech SM: ZEB1, ZEB2, and the miR-200 family form a counterregulatory network to regulate CD8+ T cell fates. J Exp Med. 2018 Feb 15; 2018 Feb 15. PMID: 29449309
- Perry CJ, Muñoz-Rojas AR, Meeth KM, Kellman LN, Amezquita RA, Thakral D, Du VY, Wang JX, Damsky W, Kuhlmann AL, Sher JW, Bosenberg M, Miller-Jensen K, Kaech SM: Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity. J Exp Med. 2018 Feb 7; 2018 Feb 7. PMID: 29436395
- Low JS, Kaech SM: Trials and Tribble-ations of tissue TRM cells. Nat Immunol. 2018 Feb. PMID: 29348504
- Weinstein JS, Laidlaw BJ, Lu Y, Wang JK, Schulz VP, Li N, Herman EI, Kaech SM, Gallagher PG, Craft J: STAT4 and T-bet control follicular helper T cell development in viral infections. J Exp Med. 2018 Jan 2; 2017 Dec 6. PMID: 29212666
- Gettinger S, Choi J, Hastings K, Truini A, Datar I, Sowell R, Wurtz A, Dong W, Cai G, Melnick MA, Du VY, Schlessinger J, Goldberg SB, Chiang A, Sanmamed MF, Melero I, Agorreta J, Montuenga LM, Lifton R, Ferrone S, Kavathas P, Rimm DL, Kaech SM, Schalper K, Herbst RS, Politi K: Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer. Cancer Discov. 2017 Dec; 2017 Oct 12. PMID: 29025772
- Laidlaw BJ, Lu Y, Amezquita RA, Weinstein JS, Vander Heiden JA, Gupta NT, Kleinstein SH, Kaech SM, Craft J: Interleukin-10 from CD4+ follicular regulatory T cells promotes the germinal center response. Sci Immunol. 2017 Oct 20. PMID: 29054998
- Yeon SM, Halim L, Chandele A, Perry CJ, Kim SH, Kim SU, Byun Y, Yuk SH, Kaech SM, Jung YW: IL-7 plays a critical role for the homeostasis of allergen-specific memory CD4 T cells in the lung and airways. Sci Rep. 2017 Sep 11; 2017 Sep 11. PMID: 28894184
- Shin HM, Kapoor VN, Kim G, Li P, Kim HR, Suresh M, Kaech SM, Wherry EJ, Selin LK, Leonard WJ, Welsh RM, Berg LJ: Transient expression of ZBTB32 in anti-viral CD8+ T cells limits the magnitude of the effector response and the generation of memory. PLoS Pathog. 2017 Aug; 2017 Aug 21. PMID: 28827827
- Roberts NA, Adams BD, McCarthy NI, Tooze RM, Parnell SM, Anderson G, Kaech SM, Horsley V: Prdm1 Regulates Thymic Epithelial Function To Prevent Autoimmunity. J Immunol. 2017 Aug 15; 2017 Jul 12. PMID: 28701508
- Wang J, Perry CJ, Meeth K, Thakral D, Damsky W, Micevic G, Kaech S, Blenman K, Bosenberg M: UV-induced somatic mutations elicit a functional T cell response in the YUMMER1.7 mouse melanoma model. Pigment Cell Melanoma Res. 2017 Jul; 2017 Jun 8. PMID: 28379630
- Ho PC, Kaech SM: Reenergizing T cell anti-tumor immunity by harnessing immunometabolic checkpoints and machineries. Curr Opin Immunol. 2017 Jun; 2017 Apr 27. PMID: 28458087
- Hajek M, Sewell A, Kaech S, Burtness B, Yarbrough WG, Issaeva N: TRAF3/CYLD mutations identify a distinct subset of human papillomavirus-associated head and neck squamous cell carcinoma. Cancer. 2017 May 15; 2017 Mar 13. PMID: 28295222
- Buck MD, Sowell RT, Kaech SM, Pearce EL: Metabolic Instruction of Immunity. Cell. 2017 May 4. PMID: 28475890
- Gray SM, Amezquita RA, Guan T, Kleinstein SH, Kaech SM: Polycomb Repressive Complex 2-Mediated Chromatin Repression Guides Effector CD8+ T Cell Terminal Differentiation and Loss of Multipotency. Immunity. 2017 Apr 18; 2017 Apr 11. PMID: 28410989
- Amezquita RA, Kaech SM: Immunology: The chronicles of T-cell exhaustion. Nature. 2017 Mar 9; 2017 Feb 22. PMID: 28225757
- Adams NM, O'Sullivan TE, Geary CD, Karo JM, Amezquita RA, Joshi NS, Kaech SM, Sun JC: NK Cell Responses Redefine Immunological Memory. J Immunol. 2016 Oct 15. PMID: 27824591
- Poholek AC, Jankovic D, Villarino AV, Petermann F, Hettinga A, Shouval DS, Snapper SB, Kaech SM, Brooks SR, Vahedi G, Sher A, Kanno Y, O'Shea JJ: IL-10 induces a STAT3-dependent autoregulatory loop in TH2 cells that promotes Blimp-1 restriction of cell expansion via antagonism of STAT5 target genes. Sci Immunol. 2016 Oct; 2016 Nov 11. PMID: 28713870
- Sowell RT, Kaech SM: Probing the Diversity of T Cell Dysfunction in Cancer. Cell. 2016 Sep 8. PMID: 27610560
- Kritikou JS, Dahlberg CI, Baptista MA, Wagner AK, Banerjee PP, Gwalani LA, Poli C, Panda SK, Kärre K, Kaech SM, Wermeling F, Andersson J, Orange JS, Brauner H, Westerberg LS: IL-2 in the tumor microenvironment is necessary for Wiskott-Aldrich syndrome protein deficient NK cells to respond to tumors in vivo. Sci Rep. 2016 Aug 1; 2016 Aug 1. PMID: 27477778
- Jung YW, Kim HG, Perry CJ, Kaech SM: CCR7 expression alters memory CD8 T-cell homeostasis by regulating occupancy in IL-7- and IL-15-dependent niches. Proc Natl Acad Sci U S A. 2016 Jul 19; 2016 Jul 6. PMID: 27385825
- Garyu JW, Uduman M, Stewart A, Rui J, Deng S, Shenson J, Staron MM, Kaech SM, Kleinstein SH, Herold KC: Characterization of Diabetogenic CD8+ T Cells: IMMUNE THERAPY WITH METABOLIC BLOCKADE. J Biol Chem. 2016 May 20; 2016 Mar 18. PMID: 26994137
- Xin A, Masson F, Liao Y, Preston S, Guan T, Gloury R, Olshansky M, Lin JX, Li P, Speed TP, Smyth GK, Ernst M, Leonard WJ, Pellegrini M, Kaech SM, Nutt SL, Shi W, Belz GT, Kallies A: A molecular threshold for effector CD8(+) T cell differentiation controlled by transcription factors Blimp-1 and T-bet. Nat Immunol. 2016 Apr; 2016 Mar 7. PMID: 26950239
- Laidlaw BJ, Craft JE, Kaech SM: The multifaceted role of CD4(+) T cells in CD8(+) T cell memory. Nat Rev Immunol. 2016 Feb; 2016 Jan 19. PMID: 26781939
- Dominguez CX, Amezquita RA, Guan T, Marshall HD, Joshi NS, Kleinstein SH, Kaech SM: The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation in response to LCMV viral infection. J Exp Med. 2015 Nov 16; 2015 Oct 26. PMID: 26503446
- Ray JP, Staron MM, Shyer JA, Ho PC, Marshall HD, Gray SM, Laidlaw BJ, Araki K, Ahmed R, Kaech SM, Craft J: The Interleukin-2-mTORc1 Kinase Axis Defines the Signaling, Differentiation, and Metabolism of T Helper 1 and Follicular B Helper T Cells. Immunity. 2015 Oct 20; 2015 Sep 22. PMID: 26410627
- Ho PC, Bihuniak JD, Macintyre AN, Staron M, Liu X, Amezquita R, Tsui YC, Cui G, Micevic G, Perales JC, Kleinstein SH, Abel ED, Insogna KL, Feske S, Locasale JW, Bosenberg MW, Rathmell JC, Kaech SM: Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses. Cell. 2015 Sep 10; 2015 Aug 27. PMID: 26321681
- Laidlaw BJ, Cui W, Amezquita RA, Gray SM, Guan T, Lu Y, Kobayashi Y, Flavell RA, Kleinstein SH, Craft J, Kaech SM: Production of IL-10 by CD4(+) regulatory T cells during the resolution of infection promotes the maturation of memory CD8(+) T cells. Nat Immunol. 2015 Aug; 2015 Jul 6. PMID: 26147684
- Cui G, Staron MM, Gray SM, Ho PC, Amezquita RA, Wu J, Kaech SM: IL-7-Induced Glycerol Transport and TAG Synthesis Promotes Memory CD8+ T Cell Longevity. Cell. 2015 May 7. PMID: 25957683
- West AP, Khoury-Hanold W, Staron M, Tal MC, Pineda CM, Lang SM, Bestwick M, Duguay BA, Raimundo N, MacDuff DA, Kaech SM, Smiley JR, Means RE, Iwasaki A, Shadel GS: Mitochondrial DNA stress primes the antiviral innate immune response. Nature. 2015 Apr 23; 2015 Feb 2. PMID: 25642965
- Mohanty S, Joshi SR, Ueda I, Wilson J, Blevins TP, Siconolfi B, Meng H, Devine L, Raddassi K, Tsang S, Belshe RB, Hafler DA, Kaech SM, Kleinstein SH, Trentalange M, Allore HG, Shaw AC: Prolonged proinflammatory cytokine production in monocytes modulated by interleukin 10 after influenza vaccination in older adults. J Infect Dis. 2015 Apr 1; 2014 Nov 2. PMID: 25367297
- Chen JH, Perry CJ, Tsui YC, Staron MM, Parish IA, Dominguez CX, Rosenberg DW, Kaech SM: Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival during chronic viral infection. Nat Med. 2015 Apr; 2015 Mar 23. PMID: 25799228
- Hu Y, Lee YT, Kaech SM, Garvy B, Cauley LS: Smad4 promotes differentiation of effector and circulating memory CD8 T cells but is dispensable for tissue-resident memory CD8 T cells. J Immunol. 2015 Mar 1; 2015 Jan 30. PMID: 25637015
- Perry RJ, Camporez JP, Kursawe R, Titchenell PM, Zhang D, Perry CJ, Jurczak MJ, Abudukadier A, Han MS, Zhang XM, Ruan HB, Yang X, Caprio S, Kaech SM, Sul HS, Birnbaum MJ, Davis RJ, Cline GW, Petersen KF, Shulman GI: Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes. Cell. 2015 Feb 12; 2015 Feb 5. PMID: 25662011
- Marshall HD, Ray JP, Laidlaw BJ, Zhang N, Gawande D, Staron MM, Craft J, Kaech SM: The transforming growth factor beta signaling pathway is critical for the formation of CD4 T follicular helper cells and isotype-switched antibody responses in the lung mucosa. Elife. 2015 Jan 8; 2015 Jan 8. PMID: 25569154
- Thakar J, Mohanty S, West AP, Joshi SR, Ueda I, Wilson J, Meng H, Blevins TP, Tsang S, Trentalange M, Siconolfi B, Park K, Gill TM, Belshe RB, Kaech SM, Shadel GS, Kleinstein SH, Shaw AC: Aging-dependent alterations in gene expression and a mitochondrial signature of responsiveness to human influenza vaccination. Aging (Albany NY). 2015 Jan. PMID: 25596819
- Backer RA, Helbig C, Gentek R, Kent A, Laidlaw BJ, Dominguez CX, de Souza YS, van Trierum SE, van Beek R, Rimmelzwaan GF, ten Brinke A, Willemsen AM, van Kampen AH, Kaech SM, Blander JM, van Gisbergen K, Amsen D: A central role for Notch in effector CD8(+) T cell differentiation. Nat Immunol. 2014 Dec; 2014 Oct 26. PMID: 25344724
- Staron MM, Gray SM, Marshall HD, Parish IA, Chen JH, Perry CJ, Cui G, Li MO, Kaech SM: The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8(+) T cells during chronic infection. Immunity. 2014 Nov 20; 2014 Nov 13. PMID: 25464856
- Laidlaw BJ, Zhang N, Marshall HD, Staron MM, Guan T, Hu Y, Cauley LS, Craft J, Kaech SM: CD4+ T cell help guides formation of CD103+ lung-resident memory CD8+ T cells during influenza viral infection. Immunity. 2014 Oct 16; 2014 Oct 9. PMID: 25308332
- Gray SM, Kaech SM, Staron MM: The interface between transcriptional and epigenetic control of effector and memory CD8⁺ T-cell differentiation. Immunol Rev. 2014 Sep. PMID: 25123283
- Gate D, Danielpour M, Rodriguez J Jr, Kim GB, Levy R, Bannykh S, Breunig JJ, Kaech SM, Flavell RA, Town T: T-cell TGF-β signaling abrogation restricts medulloblastoma progression. Proc Natl Acad Sci U S A. 2014 Aug 19; 2014 Jul 31. PMID: 25082897
- Marshall HD, Kaech SM: Regulating the diverse outcomes of interferon's interference. Trends Immunol. 2014 Aug; 2014 Jul 19. PMID: 25052591
- Ho PC, Kaech SM: BRAF-targeted therapy alters the functions of intratumoral CD4+ T cells to inhibit melanoma progression. Oncoimmunology. 2014; 2014 Jun 18. PMID: 25083331
- Ho PC, Meeth KM, Tsui YC, Srivastava B, Bosenberg MW, Kaech SM: Immune-based antitumor effects of BRAF inhibitors rely on signaling by CD40L and IFNγ. Cancer Res. 2014 Jun 15; 2014 Apr 15. PMID: 24736544
- Cui W, Joshi NS, Liu Y, Meng H, Kleinstein SH, Kaech SM: TLR4 ligands lipopolysaccharide and monophosphoryl lipid a differentially regulate effector and memory CD8+ T Cell differentiation. J Immunol. 2014 May 1; 2014 Mar 21. PMID: 24659688
- Ray JP, Marshall HD, Laidlaw BJ, Staron MM, Kaech SM, Craft J: Transcription factor STAT3 and type I interferons are corepressive insulators for differentiation of follicular helper and T helper 1 cells. Immunity. 2014 Mar 20; 2014 Mar 13. PMID: 24631156
- Kaech SM: Celebrating diversity in memory T cells. J Immunol. 2014 Feb 1. PMID: 24443505
- Shin HM, Kapoor V, Guan T, Kaech SM, Welsh RM, Berg LJ: Epigenetic modifications induced by Blimp-1 Regulate CD8⁺ T cell memory progression during acute virus infection. Immunity. 2013 Oct 17; 2013 Oct 10. PMID: 24120360
- Marshall HD, Kaech SM: Generating CD8 T cell heterogeneity: attack of the clones. Immunity. 2013 Aug 22. PMID: 23973217
- Henao-Mejia J, Williams A, Goff LA, Staron M, Licona-Limón P, Kaech SM, Nakayama M, Rinn JL, Flavell RA: The microRNA miR-181 is a critical cellular metabolic rheostat essential for NKT cell ontogenesis and lymphocyte development and homeostasis. Immunity. 2013 May 23; 2013 Apr 25. PMID: 23623381
- D'Souza AD, Parish IA, Krause DS, Kaech SM, Shadel GS: Reducing mitochondrial ROS improves disease-related pathology in a mouse model of ataxia-telangiectasia. Mol Ther. 2013 Jan; 2012 Sep 25. PMID: 23011031
- Kaech SM, Cui W: Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol. 2012 Nov; 2012 Oct 19. PMID: 23080391
- Demento SL, Cui W, Criscione JM, Stern E, Tulipan J, Kaech SM, Fahmy TM: Role of sustained antigen release from nanoparticle vaccines in shaping the T cell memory phenotype. Biomaterials. 2012 Jun; 2012 Apr 6. PMID: 22484047
- Li N, Matte-Martone C, Zheng H, Cui W, Venkatesan S, Tan HS, McNiff J, Demetris AJ, Roopenian D, Kaech S, Shlomchik WD: Memory T cells from minor histocompatibility antigen-vaccinated and virus-immune donors improve GVL and immune reconstitution. Blood. 2011 Nov 24; 2011 Sep 13. PMID: 21917752
- Cui W, Liu Y, Weinstein JS, Craft J, Kaech SM: An interleukin-21-interleukin-10-STAT3 pathway is critical for functional maturation of memory CD8+ T cells. Immunity. 2011 Nov 23. PMID: 22118527
- Marshall HD, Chandele A, Jung YW, Meng H, Poholek AC, Parish IA, Rutishauser R, Cui W, Kleinstein SH, Craft J, Kaech SM: Differential expression of Ly6C and T-bet distinguish effector and memory Th1 CD4(+) cell properties during viral infection. Immunity. 2011 Oct 28; 2011 Oct 20. PMID: 22018471
- Joshi NS, Cui W, Dominguez CX, Chen JH, Hand TW, Kaech SM: Increased numbers of preexisting memory CD8 T cells and decreased T-bet expression can restrain terminal differentiation of secondary effector and memory CD8 T cells. J Immunol. 2011 Oct 15; 2011 Sep 19. PMID: 21930973
- D'Souza AD, Parish IA, McKay SE, Kaech SM, Shadel GS: Aberrant CD8+ T-cell responses and memory differentiation upon viral infection of an ataxia-telangiectasia mouse model driven by hyper-activated Akt and mTORC1 signaling. Am J Pathol. 2011 Jun. PMID: 21641396
- Parish IA, Kaech SM: IL-7 knocks the socs off chronic viral infection. Cell. 2011 Feb 18. PMID: 21335230
- Jung YW, Rutishauser RL, Joshi NS, Haberman AM, Kaech SM: Differential localization of effector and memory CD8 T cell subsets in lymphoid organs during acute viral infection. J Immunol. 2010 Nov 1; 2010 Oct 4. PMID: 20921525
- Jung YW, Kaech SM: Like parent, like child: inheritance of effector CD8+ T cell traits. Immunity. 2010 Sep 24. PMID: 20870171
- Hand TW, Cui W, Jung YW, Sefik E, Joshi NS, Chandele A, Liu Y, Kaech SM: Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival. Proc Natl Acad Sci U S A. 2010 Sep 21; 2010 Sep 7. PMID: 20823247
- Demento SL, Bonafé N, Cui W, Kaech SM, Caplan MJ, Fikrig E, Ledizet M, Fahmy TM: TLR9-targeted biodegradable nanoparticles as immunization vectors protect against West Nile encephalitis. J Immunol. 2010 Sep 1; 2010 Jul 26. PMID: 20660705
- Cui W, Kaech SM: Generation of effector CD8+ T cells and their conversion to memory T cells. Immunol Rev. 2010 Jul. PMID: 20636815
- Poholek AC, Hansen K, Hernandez SG, Eto D, Chandele A, Weinstein JS, Dong X, Odegard JM, Kaech SM, Dent AL, Crotty S, Craft J: In vivo regulation of Bcl6 and T follicular helper cell development. J Immunol. 2010 Jul 1; 2010 Jun 2. PMID: 20519643
- Hinson ER, Joshi NS, Chen JH, Rahner C, Jung YW, Wang X, Kaech SM, Cresswell P: Viperin is highly induced in neutrophils and macrophages during acute and chronic lymphocytic choriomeningitis virus infection. J Immunol. 2010 May 15; 2010 Apr 21. PMID: 20410488
- Rutishauser RL, Kaech SM: Generating diversity: transcriptional regulation of effector and memory CD8 T-cell differentiation. Immunol Rev. 2010 May. PMID: 20536566
- Rutishauser RL, Martins GA, Kalachikov S, Chandele A, Parish IA, Meffre E, Jacob J, Calame K, Kaech SM: Transcriptional repressor Blimp-1 promotes CD8(+) T cell terminal differentiation and represses the acquisition of central memory T cell properties. Immunity. 2009 Aug 21; 2009 Aug 6. PMID: 19664941
- Parish IA, Kaech SM: Diversity in CD8(+) T cell differentiation. Curr Opin Immunol. 2009 Jun; 2009 Jun 6. PMID: 19497720
- Cui W, Joshi NS, Jiang A, Kaech SM: Effects of Signal 3 during CD8 T cell priming: Bystander production of IL-12 enhances effector T cell expansion but promotes terminal differentiation. Vaccine. 2009 Mar 26; 2009 Feb 6. PMID: 19201385
- Hand TW, Kaech SM: Intrinsic and extrinsic control of effector T cell survival and memory T cell development. Immunol Res. 2009. PMID: 18629449
- Chandele A, Joshi NS, Zhu J, Paul WE, Leonard WJ, Kaech SM: Formation of IL-7Ralphahigh and IL-7Ralphalow CD8 T cells during infection is regulated by the opposing functions of GABPalpha and Gfi-1. J Immunol. 2008 Apr 15. PMID: 18390712
- Joshi NS, Kaech SM: Effector CD8 T cell development: a balancing act between memory cell potential and terminal differentiation. J Immunol. 2008 Feb 1. PMID: 18209024
- D'Souza AD, Parikh N, Kaech SM, Shadel GS: Convergence of multiple signaling pathways is required to coordinately up-regulate mtDNA and mitochondrial biogenesis during T cell activation. Mitochondrion. 2007 Dec; 2007 Aug 16. PMID: 17890163
- Kaech SM, Wherry EJ: Heterogeneity and cell-fate decisions in effector and memory CD8+ T cell differentiation during viral infection. Immunity. 2007 Sep. PMID: 17892848
- Joshi NS, Cui W, Chandele A, Lee HK, Urso DR, Hagman J, Gapin L, Kaech SM: Inflammation directs memory precursor and short-lived effector CD8(+) T cell fates via the graded expression of T-bet transcription factor. Immunity. 2007 Aug. PMID: 17723218
- Hand TW, Morre M, Kaech SM: Expression of IL-7 receptor alpha is necessary but not sufficient for the formation of memory CD8 T cells during viral infection. Proc Natl Acad Sci U S A. 2007 Jul 10; 2007 Jul 3. PMID: 17609371
- Tesar BM, Walker WE, Unternaehrer J, Joshi NS, Chandele A, Haynes L, Kaech S, Goldstein DR: Murine [corrected] myeloid dendritic cell-dependent toll-like receptor immunity is preserved with aging. Aging Cell. 2006 Dec. PMID: 17129212
- Gao Y, Tao J, Li MO, Zhang D, Chi H, Henegariu O, Kaech SM, Davis RJ, Flavell RA, Yin Z: JNK1 is essential for CD8+ T cell-mediated tumor immune surveillance. J Immunol. 2005 Nov 1. PMID: 16237070
- Chandele A, Kaech SM: Cutting edge: memory CD8 T cell maturation occurs independently of CD8alphaalpha. J Immunol. 2005 Nov 1. PMID: 16237050