Research & Publications
Dr. Craft investigates CD4 T helper cells in conventional and autoimmune responses in mice and in humans, focusing upon differentiation and function of follicular helper T (Tfh) cells that promote B cell maturation. Tfh-cell dependent GC responses are critical for development of humoral immunity upon vaccine administration or infection, and for driving pathogenic autoreactive B cell responses in autoimmunity. Dr. Craft’s studies on Tfh cells build upon his earlier work in characterizing immune targets in lupus, and studies of tolerance, inflammation, and therapy. His lab also investigates other CD4 T cell populations, including those that promote immune memory and inflammation. Studies by individuals in his lab include those by graduate student Amanda Poholek, in collaboration with Shane Crotty and colleagues, demonstrated that the transcription factor Bcl6 is necessary and sufficient for Tfh-cell genesis. Upon activation, CD4 T cells exhibit metabolic changes to meet their proliferative and effector needs, with the understanding of how metabolism is regulated in T helper (Th) 1 and Tfh cells incomplete. Work by grad students John Ray and Justin Shyer, with Matt Staron in Sue Kaech’s lab, was the first to decipher metabolic events that dictate Tfh-cell vs. Th1 cell development. Shyer and postdoctoral fellow Will Bailis in the Flavell lab at Yale subsequently used a CRISPR/Cas9 screen in primary T cells to reveal metabolic requirements for Th cell proliferation and effector function, a tool that will further aid identification of metabolic pathways needed for Tfh vs. Th1 differentiation. More recent work done by Can Cui, a student in the lab co-mentored by Nik Joshi, has shown a unique role to Tfh-B cell interactions in promoting effector CD8 T cell responses in a tumor model. Ping-Min Chen, a graduate student, demonstrated that upon renal infiltration, T cells adapt to their environment to ensure survival and effector capability, with remodeling of metabolic and epigenetic pathways with tissue damage driven by a hypoxia-dependent inflammatory gene program, which can be therapeutically blocked in lupus models with reversal of tissue damage.
Specialized Terms: T cell development, T cell differentiation and function, autoimmunity; lupus; tolerance
Extensive Research Description
Ongoing studies are targeted towards identification of the developmental pathways of CD4 T cells that provide B cell help and that promote inflammation, and dissection of their potential to promote autoimmunity and inflammation. Related work involves determination of tissue environmental factors that regulate T cell metabolism and effector function at inflammatory sites, such as tissues damaged in autoimmunity.
Antigens, Differentiation, T-Lymphocyte; Autoimmune Diseases; Biology; Immunity; Lupus Erythematosus, Systemic; Investigative Techniques; Rheumatology; Cytokines