CD4+ T cell memory

Abstract

Specialized subpopulations of CD4⁺ T cells survey major histocompatibility complex class II-peptide complexes to control phagosomal infections, help B cells, regulate tissue homeostasis and repair or perform immune regulation. Memory CD4⁺ T cells are positioned throughout the body and not only protect the tissues from reinfection and cancer, but also participate in allergy, autoimmunity, graft rejection and chronic inflammation. Here we provide updates on our understanding of the longevity, functional heterogeneity, differentiation, plasticity, migration and human immunodeficiency virus reservoirs as well as key technological advances that are facilitating the characterization of memory CD4⁺ T cell biology.

Fig. 1 |. Dynamics of a CD4⁺ T cell response.

1. Naive CD4⁺ T cells quiescently recirculate through blood (dark red) and lymphoid (light green) tissues. Upon infection, for example by a respiratory pathogen, APCs migrate from infected barrier sites (magenta) to the draining lymph nodes through afferent lymphatics and present peptides from the pathogen on MHC-II molecules. 2. Recognition of the peptide–MHC-II complex through TCR in combination with co-stimulation and cytokine signals lead to the activation, differentiation and expansion of naive CD4⁺ lymph node T cells. 3. CD4⁺ T cells proliferate and differentiate into various effector subsets that each become poised to make specialized contributions to immunity. 4. Many proliferated T cells leave the lymph nodes and migrate to the infected tissue through blood to assist in pathogen control at sites of infection. 5. Once the infection is cleared, most pathogen-specific CD4⁺ T cells die resulting in contraction of the population. 6. However, a few survive to establish long-lived memory and stay widely distributed across the body. 7. Upon reinfection, memory CD4⁺ T cells can mount anamnestic responses that are quicker and of higher magnitude than a primary response.

Fig. 2 |. CD4⁺ T cell differentiation is tailored to specific classes of immunogens.

Naive CD4⁺ T cells differentiate into specialized effector subsets that support cell-mediated or humoral responses. Intracellular pathogens induce T-bet-expressing T helper (T_H) 1 cells that secrete IFNγ to potentiate CD8⁺ T cell and macrophage responses. Extracellular parasites induce GATA3-expressing T_H2 cells that secrete IL-4, IL-5 and IL-13 to recruit and activate mast cells, eosinophils or basophils. Extracellular bacteria or fungi trigger the formation of RORγt-expressing T_H17 cells that produce IL-17 to trigger neutrophil responses. In parallel, immunogens induce Bcl6-expressing T_FH cells that receive help from B cells through ICOS and in turn promote humoral responses by providing CD40L and cytokines to B cells through direct cell-to-cell interaction, triggering isotype switching, affinity maturation and differentiation into memory or antibody-secreting cells. T_FH cells take on some characteristics of their cell-mediated response counterparts, expressing low levels of T-bet, GATA3 or RORγt, leading to biased secretion of IFNγ, IL-4 or IL-17 and skewing the antibody response toward specific isotypes.

Fig. 3 |. Memory CD4⁺ T cell heterogeneity and ontogeny.

a, Memory CD4⁺ T cells exhibit heterogeneity in many parameters, including function, migration, location, developmental plasticity and proliferative potential. This makes categorization of defined subsets challenging. b, Existing memory CD4⁺ T cell differentiation schemes. Left, excludes memory T_FH cells. Middle, specifies memory T_FH cells, but excludes the concept of T_CM cells. Right, includes both memory T_FH cells and T_CM cells. T_FH cells might differentiate directly from activated naive CD4⁺ T cells, or come from a common T_CM cell precursor.

Fig. 4 |. Immunosurveillance by CD4⁺ T cells.

Memory CD4⁺ T cell immunosurveillance strategy after a respiratory viral infection that elicits a type I response. Although we focus on memory T_H1 cells, both memory T_H2 and memory T_H17 cells have been well documented to take up permanent residence in NLTs. In contrast to T_H1 T_CM cells, which express CD62L, many memory T_H1 cells cannot access lymph nodes (LN) through high endothelial venules. These memory T_H1 cells in lymph nodes might represent T_H1 cells that recirculate constitutively through NLTs and enter lymph nodes through afferent lymphatics (‘backdoor entry’) from upstream NLTs, or SLO-resident memory T_H1 cells. Memory T_H1 cells in the blood comprise blood restricted cells, NLT recirculators and T_CM cells. FR4^hi memory T_FH cells populate SLOs and may reside at the outer boundaries of B cell follicles. T_FH-like CD4⁺ T_RM cells have been identified in lungs of influenza-infected mice. In contrast to resident T_H1 cells, resident T_FH cells seem locally restricted to TLSs.