Inducible costimulator regulates effector CD4 T cell trafficking and maintenance of memory CD4 T cells

Inducible costimulator (ICOS) is a member of the CD28 family of costimulatory receptors. ICOS has previously been shown to enhance CD4 T cell proliferation and differentiation in multiple in vitro and in vivo models. ICOS enhances tissue inflammation in many mouse models, which has been attributed to the effects of ICOS costimulation on proliferation and differentiation. Few studies have directly addressed the role of ICOS costimulation in the migration of activated CD4 T cells. In the first part of this thesis, I demonstrate that ICOS costimulation regulates activated CD4 T cell migration to the lymph nodes, by inducing down-regulation of CCR7 and CD62L. By reducing CD4 T cell migration to lymph nodes, ICOS may augment T cell differentiation and T cell migration to the tissues. Although our studies and others have shown that ICOS costimulation can enhance CD4 T cell proliferation and increase the number of activated cells, few studies have addressed the role of ICOS in the development and maintenance of memory cells which arise from activated cells. In the second part of this thesis, I demonstrate that ICOS costimulation regulates the development of effector memory phenotype CD4 T cells and the maintenance of antigen-specific effector memory CD4 T cells but has no effect on central memory CD4 T cells. By enhancing the maintenance of effector memory cells, ICOS costimulation promotes memory CD4 T cell-mediated responses, including effector cytokine production and protection from re-infection. This thesis therefore describes two novel mechanisms by which ICOS costimulation can augment protective and pathological CD4 T-cell mediated responses.