The architectural design of CD8+ T cell responses in acute and chronic infection: Parallel structures with divergent fates

Abstract

In response to infection, T cells adopt a range of differentiation states, creating numerous heterogeneous subsets that exhibit different phenotypes, functions, and migration patterns. This T cell heterogeneity is a universal feature of T cell immunity, needed to effectively control pathogens in a context-dependent manner and generate long-lived immunity to those pathogens. Here, we review new insights into differentiation state dynamics and population heterogeneity of CD8+ T cells in acute and chronic viral infections and cancer and highlight the parallels and distinctions between acute and chronic antigen stimulation settings. We focus on transcriptional and epigenetic networks that modulate the plasticity and terminal differentiation of antigen-specific CD8+ T cells and generate functionally diverse T cell subsets with different roles to combat infection and cancer.

Figure 1.

Heterogeneous immune populations in virus infection model. In both acute and chronic infection, early effector (EE) cells differentiate in a parallel manner into various CD8⁺ T cell subsets. Notable distinctions in trafficking patterns are signified by residence in lymphoid organs (gray), blood (red), or peripheral tissues (green). In acute infection, several effector and memory states are found. TE cells are typically found in the red pulp of spleen or blood, whereas MP cells are primarily found in white pulp or lymphoid structures, but they are also capable of recirculation. T_CM and T_EM cells both circulate in the blood, but T_CM cells predominate in lymphoid organs, whereas T_EM cells are also found in tissues. T_PM cells are proposed to circulate throughout lymph, blood, and tissues. T_RM cells do not circulate much and reside long-term in tissues. As in acute infection, heterogeneous states and distinct localization of CD8⁺ T cells are found in chronic infection. Tex_prog and MP cells are often observed in lymphoid structures, yet their circulation tendency might not be equivalent. Tex_int and Tex_term cells are predominantly found in blood and peripheral tissue, respectively.

Figure 2.

Heterogeneous T cell subsets in both acute and chronic infection are possibly driven by a similar mechanism. (A) In acute infection, depending on T cell activation and inflammation intensity, heterogeneous MP cells are formed with various levels of CX3CR1, which give rise to diverse memory subsets. KRLG1^hi IL-7Ra^hi or exKLRG1 MP cells develop memory cells of higher cytotoxicity (Herndler-Brandstetter et al., 2018; Olson et al., 2013). (B) Several memory subsets maintain plasticity, which allows homeostatic (T_RM to T_CM; T_EM or T_PM to T_CM) or antigen rechallenge–induced (T_CM to T_EM, T_PM, or T_RM) cell state conversion (Marzo et al., 2005, 2007; Beura et al., 2018b; Park et al., 2018; Osborn et al., 2019; Fonseca et al., 2020; Frizzell et al., 2020; Wherry et al., 2003b; Wherry and Ahmed, 2004; Bouneaud et al., 2005; Gattinoni et al., 2011; Gerlach et al., 2016). (C) Parallel differentiation ontology in chronic infection. Tex_prog cells diverge from EE due to TOX and Tcf7 activation, which suppresses TE-like cell formation. Tex_prog further differentiate in a linear manner, or also perhaps in a bifurcated manner, to Tex_int or Tex_term cells. (D) Transcription gradient model for both acute and chronic infection. Shared TF gradients and surface receptors are found that drive the proliferative, stem cell–like cell states to more terminally differentiated cell states with effector function. KRLG1 expression is found in TE in acute and TE-like cells in chronic LCMV clone 13 and exhausted cells in HIV-infected patients. N, naive; SLO, secondary lymphoid organs.

Figure 3.

Transcriptional meta-analysis of T cell subsets in both acute and chronic infection. Scaled and batch-corrected RNA-sequencing expression from sorted effector and exhausted cell populations (Dominguez et al., 2015; Mackay et al., 2016; Hudson et al., 2019; Milner et al., 2020a; Renkema et al., 2020). T cell states that arise during chronic and acute infection can be characterized by similar transcriptional archetypes, such as up-regulation of sets of stem-like genes (Tex_prog and MP cells), cytotoxicity and circulating potential (Tex_int, TE, and LLE cells), or inhibitory receptor genes (Tex_term and T_RM cells).