Foreign antigen-independent memory-phenotype CD4+ T cells: a new player in innate immunity?

Abstract

Memory-phenotype CD8⁺ T cells exist in substantial numbers within hosts that have not been exposed to either foreign antigen or overt lymphopenia. These antigen-inexperienced memory-phenotype T cells can be divided into two major subsets: ‘innate memory’ T cells and ‘virtual memory’ T cells. Although these two subsets are nearly indistinguishable by surface markers alone, notable developmental and functional differences exist between the two subsets, which suggests that they represent distinct populations. In this Opinion article, we review the available literature on each subset, highlighting the key differences between these populations. Furthermore, we suggest a unifying model for the categorization of antigen-inexperienced memory-phenotype CD8⁺ T cells.

Figure 1. A model of the development of innate memory and virtual memory T cells.

Innate memory T (T_IM) cell development: in the thymus, naive CD8⁺ T cells are exposed to interleukin-4 (IL-4) derived from promyelocytic leukaemia zinc finger (PLZF)-expressing thymocytes and convert into T_IM cells. In the periphery, the presence of T_IM cells is dependent on IL-15, either because it is necessary for T_IM cells to exit the thymus or because it is necessary for their survival once they are in the periphery. Although T_IM cells in the thymus do not express T-bet, all antigen-inexperienced memory-phenotype CD8⁺ T cells in the periphery (defined by a CD44^hiCD49d^lowCD122^hi phenotype) express both eomesodermin (EOMES) and T-bet. This suggests that the majority of T_IM cells in the periphery have encountered IL-15, which results in their phenotype becoming indistinguishable from that of virtual memory T (T_VM) cells. T_VM cell development: naive CD8⁺ T cells expressing T cell receptors (TCRs) with a strong affinity for self-peptide–MHC complexes express high levels of CD5, exit the thymus and convert into T_VM cells following their interaction with IL-15 that is trans-presented by lymphoid-resident CD8α⁺ dendritic cells (DCs). IL-4 may act on existing T_VM cells to further expand the T_VM cell population, which depends on IL-15 for survival. Dashed arrows indicate differentiation. IL −4R, IL-4 receptor.

Figure 2. The influence of cytokine complexes on naive and memory CD8+ T cell subsets.

a | Interleukin-15 (IL-15)–IL-15 receptor subunit-α (IL-15Rα) complexes induce a substantial expansion of cells with a virtual memory T (T_VM) phenotype. This most likely occurs through the combined effects of (i) stimulation and expansion of thymic-emigrant innate memory T (T_IM) cells, (ii) the conversion of naive CD8⁺ T cells that have more moderate levels of CD5 expression (with lower self-affinity) and (iii) the expansion of the pre-existing T_VM cell pool. By contrast, IL-4 cytokine–antibody complexes promote the conversion of both naive and T_VM cells into distinct populations of ‘IL-4-induced’ memory-phenotype cells, expanding them in the process. b | The main phenotypical characteristics of these three memory-phenotype populations (namely, T_VM cells, T_IM cells and ‘IL-4-induced’ memory-phenotype cells) are shown. CXCR3, CXC-chemokine receptor 3; EOMES, eomesodermin.