IL-21 in Homeostasis of Resident Memory and Exhausted CD8 T Cells during Persistent Infection

Abstract

CD4 T cells guide the development of CD8 T cells into memory by elaborating mitogenic and differentiation factors and by licensing professional antigen-presenting cells. CD4 T cells also act to stave off CD8 T cell dysfunction during repetitive antigen stimulation in persistent infection and cancer by mitigating generation of exhausted T cells (T_EX). CD4 T cell help is also required for establishing and maintaining tissue-resident memory T cells (T_RM), the nonrecirculating memory T cell subset parked in nonlymphoid tissues to provide frontline defense against reinvading pathogens. Interleukin (IL)-21 is the signature cytokine secreted by follicular helper CD4 T cells (T_FH) to drive B cell expansion and differentiation in germinal centers to mount high-affinity, isotype class-switched antibodies. In several infection models, IL-21 has been identified as the CD4 T help needed for formation and survival of T_RM and T_EX. In this review, we will explore the different memory subsets of CD8 T cells in persistent infections, the metabolic profiles associated with each, and evidence documenting the importance of CD4 T cell-derived IL-21 in regulating CD8 T_RM and T_EX development, homeostasis, and function.

Keywords: CD4 T cells; CD8 T cells; exhaustion; interleukin (IL)-21; persistent infection; resident memory.

Figure 1

CD8 T cell memory subsets. CD8 T cells are classified as various memory subsets based on their expression of certain transcription factors, surface molecules, and metabolic profiles. As depicted here, there is fluidity and overlap in these memory profiles. Figure image created with BioRender.com.

Figure 2

Proposed model of CD4 T cell-derived IL-21 help to CD8 T cells in the brain during PyV-infection. (A) CD4 T cells with a high density of high-affinity TCRs are CXCR5^hiPD-1^hi and produce IL-21 that is received by the CD8 T cells in the brain. This is likely occurring around 15 dpi. (B) IL-21 binds to the IL21R on CD8 T cells and starts a signaling cascade that helps guide their differentiation into bT_RM, metabolically, phenotypically, and functionally. ETC, electron transport chain. Figure image created with BioRender.com.