Shaping Heterogeneity of Naive CD8+ T Cell Pools

Abstract

Immune diversification helps protect the host against a myriad of pathogens. CD8⁺ T cells are essential adaptive immune cells that inhibit the spread of pathogens by inducing apoptosis in infected host cells, ultimately ensuring complete elimination of infectious pathogens and suppressing disease development. Accordingly, numerous studies have been conducted to elucidate the mechanisms underlying CD8⁺ T cell activation, proliferation, and differentiation into effector and memory cells, and to identify various intrinsic and extrinsic factors regulating these processes. The current knowledge accumulated through these studies has led to a huge breakthrough in understanding the existence of heterogeneity in CD8⁺ T cell populations during immune response and the principles underlying this heterogeneity. As the heterogeneity in effector/memory phases has been extensively reviewed elsewhere, in the current review, we focus on CD8⁺ T cells in a "naïve" state, introducing recent studies dealing with the heterogeneity of naive CD8⁺ T cells and discussing the factors that contribute to such heterogeneity. We also discuss how this heterogeneity contributes to establishing the immense complexity of antigen-specific CD8⁺ T cell response.

Keywords: Cytokine; Heterogeneity; Homeostasis; Naive T-cell; Self-antigen.

Figure 1. Heterogeneity of naive CD8⁺ T cells and factors shaping the heterogeneity. (A) Phenotypic and functional heterogeneity can be observed in naive CD8⁺ T cell subsets exhibiting different levels of various surface molecules. These proteins are all functionally relevant for variety of T cell responses, including T cell survival and basal turn-over in a steady state (CD127 and GM1), as well as T cell activation/proliferation (CD5, CD8, CD45, and GM1) and migration into non-lymphoid tissues (Ly6C and CD183) during antigenic stimulation. (B) Several factors contribute to shaping the heterogeneity of naive CD8⁺ T cells in a steady state, which includes tonic TCR signaling via self-ligand interactions (self-pMHC), homeostatic cytokines (IL-4, IL-7, IL-15, type I IFN, and TGF-β), as well as a certain age-associated cue.

Figure 2. Schematic of how heterogeneity of naive CD8⁺ T cells is formed and its physiological implications. Naive CD8⁺ T cell heterogeneity can be formed by various factors derived from thymic developmental and peripheral homeostatic phases, which creates immense diversity and complexity of T cell immune responses. For example, the relatively low (CD5^lo) or high (CD5^hi) intrinsic self-reactivity of naive CD8⁺ T cell subsets shows enhanced MPEC and SLEC skewing, respectively. For SLEC skewing of CD5^hi subsets (especially for Ly6C⁺ subset), preconditioning of tonic type I IFN is crucial. Likewise, tonic TGF-β preconditioning plays a role in T_RM differentiation. Developmental origin (adult layer vs. fetal layer T_N) of naive CD8⁺ T cells is also associated with shaping the fate of effector differentiation.

T_N, naive T.