Protecting and rescuing the effectors: roles of differentiation and survival in the control of memory T cell development

Abstract

Vaccines, arguably the single most important intervention in improving human health, have exploited the phenomenon of immunological memory. The elicitation of memory T cells is often an essential part of successful long-lived protective immunity. Our understanding of T cell memory has been greatly aided by the development of TCR Tg mice and MHC tetrameric staining reagents that have allowed the precise tracking of antigen-specific T cell responses. Indeed, following acute infection or immunization, naïve T cells undergo a massive expansion culminating in the generation of a robust effector T cell population. This peak effector response is relatively short-lived and, while most effector T cells die by apoptosis, some remain and develop into memory cells. Although the molecular mechanisms underlying this cell fate decision remain incompletely defined, substantial progress has been made, particularly with regards to CD8(+) T cells. For example, the effector CD8(+) T cells generated during a response are heterogeneous, consisting of cells with more or less potential to develop into full-fledged memory cells. Development of CD8(+) T cell memory is regulated by the transcriptional programs that control the differentiation and survival of effector T cells. While the type of antigenic stimulation and level of inflammation control effector CD8(+) T cell differentiation, availability of cytokines and their ability to control expression and function of Bcl-2 family members governs their survival. These distinct differentiation and survival programs may allow for finer therapeutic intervention to control both the quality and quantity of CD8(+) T cell memory. Effector to memory transition of CD4(+) T cells is less well characterized than CD8(+) T cells, emerging details will be discussed. This review will focus on the recent progress made in our understanding of the mechanisms underlying the development of T cell memory with an emphasis on factors controlling survival of effector T cells.

Keywords: Bcl-2; Bim; CD8+ T cells; KLRG1hiCD127lo; memory cells.

FIGURE 1

Kinetics of T cell response after acute viral infection. Graph shows total numbers (y-axis) of antigen-specific CD8⁺ (blue) and CD4⁺ (red) T cells days (x-axis) after acute infection as modified from Hinds et al. (2007). Kinetics of viral load (orange) is also displayed on the graph.

FIGURE 2

Pathways governing the survival and differentiation of effector CD8⁺ T cells. The differentiation of early effector cells (KLRG1^loCD127^lo) into KRLG1^hiCD127^lo or KLRG1^loCD127^hi cells is regulated by inflammatory cytokines and by IL-10 and IL-21. IL-12 can activate STAT4 and PI-3K signaling which modulates mTOR kinases and subsequent Akt phosphorylation at s473. Phosphorylated Akt can phosphorylate and inactivate FOXO proteins. This favors an increased t-bet:eomes ratio and differentiation into KLRG1^hiCD127^lo cells. On the other hand, Stat3 phosphorylation by IL-10 and IL-21 increases eomes and other transcription factors required for differentiation of KLRG1^loCD127^hi cells. SOCS3 induced by Stat3 can, then, inhibit IL-12 signaling, effectively shielding KLRG1^loCD127^hi cells from inflammation. Interestingly, survival of effector subsets are regulated by γc cytokines IL-15 and IL-7 via signals driven through STAT5 which appear largely independent of differentiation. While KLRG1^hiCD127^lo cells can only receive IL-15 signals; IL-15 and IL-7 can both activate Stat5 signaling in KLRG1^loCD127^hi cells. This results in Bcl-2 upregulation and inhibition of Bim-mediated apoptosis. IL-15 becomes limiting for KLRG1^hiCD127^lo cells reducing their ability to sustain Bcl-2 levels in the face of TGF-β signaling. Id2 may also control Bim levels in KLRG1^hiCD127^lo cells. FOXO proteins may be at the intersection of survival and differentiation pathways as it can regulate both Bim expression and influence the t-bet:eomes ratio.