Memory CD4+ T Cells in Immunity and Autoimmune Diseases

Abstract

CD4⁺ T helper (Th) cells play central roles in immunity in health and disease. While much is known about the effector function of Th cells in combating pathogens and promoting autoimmune diseases, the roles and biology of memory CD4⁺ Th cells are complex and less well understood. In human autoimmune diseases such as multiple sclerosis (MS), there is a critical need to better understand the function and biology of memory T cells. In this review article we summarize current concepts in the field of CD4⁺ T cell memory, including natural history, developmental pathways, subsets, and functions. Furthermore, we discuss advancements in the field of the newly-described CD4⁺ tissue-resident memory T cells and of CD4⁺ memory T cells in autoimmune diseases, two major areas of important unresolved questions in need of answering to advance new vaccine design and development of novel treatments for CD4⁺ T cell-mediated autoimmune diseases.

Keywords: CD4+ T cells; autoimmune disease; central memory T cell; effector memory T cell; memory T cells; tissue-resident T cell.

Figure 1

Developmental models of memory T cells: (a) In the linear model, effector T cells or memory precursor cells (yellow) are generated following activation of naïve T cell by antigen-presenting cells (APCs) presenting peptide on major histocompatibility complex (MHC) molecules. The intermediate effectors or memory precursors give rise to mature effector memory T cells (T_EM) (red) and central memory T cells (T_CM) (blue). It remains to be answered if the intermediate effectors/precursors also give rise to tissue-resident memory T cells (T_RM) (b) In the asymmetrical model, the proximal daughter cells to the immune-synapse (naïve T cell- T cell receptor (TCR) + peptide and MHC-APC) develop into T_EM, while the distal daughter cells develop into T_CM. It is currently unknown which cells give rise to T_RM (green). (c) In the self-renewal model self-renewing effector T cells or T_CM are generated from naïve T cells. These self-renewing cells can then give rise to T_EM cells. It is unresolved if T_RM are generated from self-renewing T_CM/effector cells or from T_EM. (d) In the simultaneous model naïve T cells first differentiate into different T cell subsets. T cell subsets give rise to different memory subsets as follows: Th1 and Th17 cells (dark gray) generate T_EM, while T_FH cells (light gray) generate T_CM. The T helper cell subset(s) that generate T_RM has not yet been identified.

Figure 2

Factors influencing memory T cell development: Naïve T cells are activated by peptide and MHC via TCR. High levels of interleukin (IL)-2 are critical during early TCR engagement for memory-cell development. The memory T cell development fate is dependent on the inflammatory milieu and TCR signaling strength. Increased levels of inflammatory signals favor T_EM generation and decreased levels of these signals favor T_CM. Conversely, increased levels of TCR affinity and precursor frequencies favor T_CM development while decreased levels favor T_EM. TGF-β is important for generating T_RM. How other inflammatory signals and TCR signaling strength affect T_RM generation remains unresolved.

Figure 3

Markers of memory T cell subsets and their precursors: Terminally differentiated T_CM (blue) and T_EM (red) can be distinguished based on the expression of CD62L, CCR7, IL7R, and other markers not shown. T_RM can be further characterized based on the expression of KLF2, IL-15R, CD103, and S1PR1. T_CM can give rise to T_EM and vice versa. *Recent data suggested that T_RM can re-enter the circulation.