The role of inducible costimulator-mediated phosphoinositide 3-kinase activation in the differentiation and function of follicular helper T cells

Antibodies are crucial components of the adaptive immune arsenal against invading pathogens. Production of high-affinity class-switched antibodies relies on follicular helper T (Tfh) cells, a distinct subset of CD4 helper T cells that migrate into B cell follicles and promote B cell differentiation into plasma cells during germinal center (GC) reactions. The CD28-like costimulatory receptor Inducible Costimulator (ICOS) is expressed on the surface of activated T cells and is crucial for the generation of Tfh cells in mice and humans, but the molecular mechanisms remained unknown. ICOS had been known as a potent activator of phosphoinositide 3-kinase (PI3K), but the role of ICOS-mediated PI3K activation in T cells has been poorly understood. The work presented here is a compilation of two studies that highlight the unique role of PI3K in ICOS-mediated Tfh cell differentiation and function. In the first study, presented in Chapter II, I analyzed a knock-in strain of mice possessing a point mutation in the cytoplasmic tail of ICOS that prevents binding of PI3K (ICOS-YF). I show that ICOS-mediated PI3K activation is crucial for the generation of Tfh cells, and in turn, GC formation, antibody class-switch, and affinity maturation. The ICOS-PI3K axis was crucial for the potentiation of T cell receptor (TCR)-mediated expression of IL-21 and IL-4, key cytokines involved in T cell-mediated B cell help. I also show data that strongly suggests that ICOS and CD28 have differential roles in the multistep process of Tfh cell differentiation, where CD28 is mainly involved in the early expansion of CD4 T cells through non-PI3K signaling mechanisms, while ICOS is involved in the later stages of Tfh cell differentiation in a PI3K-dependent manner. In the study presented in Chapter III, I show that ICOS costimulation enhances TCR-mediated activation of the key translation mediators 4E-BP1 and S6K, in a manner dependent on PI3K. Consistently, I show that the ICOS-PI3K axis enhances the formation of polysomes on IL-4 mRNA. Using an in vitro T-B cell co-culture system, I provide evidence that ICOS mutant CD4 T cells have impaired ability to induce B cell differentiation due to a limited production of IL-4. These findings suggest that ICOS-PI3K signaling facilitates targeted delivery of IL-4 from helper T cells to cognate B cells during T cell-B cell interactions in the GC. Thus, I demonstrate that PI3K is a key downstream signaling component in ICOS signaling during Tfh cell generation. I also show that ICOS-PI3K signaling can alter translational efficiency of pre-existing mRNAs suggesting ICOS' potential role in regulating the function of Tfh cells.

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