The Role of γ_с Cytokines in T Cell Development, T Cell Homeostasis and CD8+ T Cell Function: A Dissertation

Abstract

T lymphocytes are essential components of the immune system and as such are continually regulated by a variety of factors. Every step of their development, survival and function is tightly monitored to ensure their ability to recognize most foreign agents and mount adaptive immune responses during pathogenic infections, while remaining tolerant to self-antigens. Among the many factors that participate in the regulation of T cell development and function are the cytokines. Cytokines that signal through the common gamma (γс) chain and the Janus kinase 3 (Jak3) include IL-2, -4, -7, -9, -15, and -21 and have been implicated in the regulation of every stage in the life of a T cell. Therefore, it is not surprising that mutations in the γс chain or Jak3 lead to a SCID condition in humans and mice. Specifically, Jak3-deficient mice are characterized by a reduction in thymic cellularity and dysregulated T cell homeostasis. They have an expansion of memory-like CD4+ mature T cells and an almost complete absence of mature CD8+ T cells. By investigating the TCR repertoire of CD4+ T cells in the thymus and spleen of Jak3-/- mice, I deduced that the CD4+ T cell activation and expansion is TCR-specific and takes place in the periphery of the mice. After crossing Jak3-deficient mice to Bcl-2 transgenic mice I showed that the developmental block observed in Jak3-/- mice could not be rescued by the anti-apoptotic factor, despite the fact that its expression did increase, slightly, the total numbers of developing thymocytes. The enforced expression of Bcl-2 was also not sufficient to revert the dysregulation of T cell homeostasis in Jak3-/- mice. Finally, in order to further understand the role played by γс cytokines during T cell function, I investigated the ability of mature Jak3-/- CD8+ T cells to become activated and differentiate into effector cells in response to a viral infection. My results indicate that CD8+ T cells are activated and proliferate in response to a viral infection, but their survival, as well as their ability to proliferate and differentiate into effector cells are greatly impaired, resulting in the inability of Jak3-deficient mice to mount a protective response.