Roles of CD28, Inducible Costimulator, and the Interleukin-2 receptor in helper T cell memory formation.

University of Minnesota Ph.D. dissertation. August 2012. Major: Microbiology, Immunology and Cancer Biology. Advisor: Dr. Marc Jenkins. 1 computer file (PDF); viii, 132 pages.Numerous studies have suggested that CD28, Inducible Costimulator (ICOS), and Interleukin-2 receptor (IL-2R) signals shape the size and composition of the helper T cell memory pool, but the extent to which these signals regulate specific aspects of memory formation and the precise mechanisms of these processes remain unclear. To address this question, we used a sensitive peptide:Major Histocompatibility Complex II (p:MHCII) tetramer and magnetic bead-based enrichment method to track p:MHCII-specific helper T cells in mice throughout the course of an immune response. We found that CD28, ICOS, and the IL-2R each control unique aspects of helper T cell memory formation. The major defect in CD28-deficient T cells was a failure to sustain the proliferation of effector T cells and not a defect in memory formation per se; CD28-deficient T cells produced memory cells proportionate to the number of effectors present at the peak of the response. Our findings suggest that CD28 mediates this process by enhancing TCR-dependent NFκB signaling independently of the two CD28 cytoplasmic tail sequences previously implicated in clonal expansion. In contrast, ICOS or IL-2R deficiency did not grossly reduce the overall size of the effector or memory cell populations. Instead, they controlled the generation of two distinct subsets of memory T cells from effector cells that were present several days after infection. T-bethigh T helper type-1 effector memory (Th1em) cells were generated in an IL-2R-dependent fashion. In contrast, T-betlow CC chemokine receptor 7 (CCR7)+ CXC cheomokine receptor 5 (CXCR5)+ central memory T (Tcm) cells were formed in a Bcl6- and ICOS-dependent manner from T follicular helper (Tfh) effector cells. Thus, CD28, ICOS, and IL-2R regulate distinct aspects of helper T cell memory formation