Impact of HIV Infection and HAART Therapy on CD4 T Helper Cell Subset Expression and Function

1.1 Th cell development Regulation of T helper (Th) cell differentiation and proliferation depends on which cytokines are present in the microenvironment of a naive Th cell. Induction of specific transcription factors results in programming of the naive Th0 cell into one of several subsets. Currently there are four well characterized Th cell subsets, namely Th1, Th2, Th17, and the T regulatory (Treg) cells (Figure 1). In this chapter we will be focusing on the Th1, Th17, and Treg cell populations. However, at this point it is also worth mentioning the relatively newly described Th9 and follicular (Tfh) cell subsets. Here we briefly discuss the differentiation pathways taken by a Th0 cell that ultimately results in the formation of these different subsets. Since the early 1980’s, the Th1/Th2 paradigm has been well-studied. Th1 cells are known for expression of the signature cytokine IFN-┛ and resulting anti-viral activities. The necessary driving cytokine for these cells is IL-12 in conjunction with the Th1-specific transcription factor T-bet (Hsieh, Macatonia et al., 1993; Seder, Gazzinelli et al., 1993;Szabo, Sullivan et al., 2002). IL-27, related to IL-12, has been recently shown to play a role in the induction of Th1 cells, while also actively repressing development of other subsets. On the other hand, Th2 cells are largely recognized to support humoral immunity and are induced by the presence of IL-4 and resulting activation of the STAT6 transcription factor(Kaplan, Schindler et al., 1996;Kurata, Lee et al., 1999). Equally important is the activation of the GATA binding protein 3 (GATA-3), the main regular of Th2 development (Pai, Truitt et al., 2004;Zhu, Min et al., 2004). The newly defined Th17 cells have been implicated in a number of inflammatory disorders and are recognized as key Th cells that trigger massive proinflammatory responses. They are characterized by production of IL-17 and differentiation of these cells requires both tumor growth factor (TGF)-β and IL-6 which act together to promote development of the Th17 subset (Bettelli, Carrier et al., 2006; Mangan, Harrington et al., 2006). Additionally important to the generation of these cells is IL-23, which functions to aid in the development and proliferation of Th17 cells. The key transcription factors required belong to the retinoic acid-related orphan receptors (ROR)