Memory T follicular helper CD4 T cells

Abstract

T follicular helper (Tfh) cells are the subset of CD4 T helper cells that are required for generation and maintenance of germinal center reactions and the generation of long-lived humoral immunity. This specialized T helper subset provides help to cognate B cells via their expression of CD40 ligand, IL-21, IL-4, and other molecules. Tfh cells are characterized by their expression of the chemokine receptor CXCR5, expression of the transcriptional repressor Bcl6, and their capacity to migrate to the follicle and promote germinal center B cell responses. Until recently, it remained unclear whether Tfh cells differentiated into memory cells and whether they maintain Tfh commitment at the memory phase. This review will highlight several recent studies that support the idea of Tfh-committed CD4 T cells at the memory stage of the immune response. The implication of these findings is that memory Tfh cells retain their capacity to recall their Tfh-specific effector functions upon reactivation to provide help for B cell responses and play an important role in prime and boost vaccination or during recall responses to infection. The markers that are useful for distinguishing Tfh effector and memory cells, as well as the limitations of using these markers will be discussed. Tfh effector and memory generation, lineage maintenance, and plasticity relative to other T helper lineages (Th1, Th2, Th17, etc.) will also be discussed. Ongoing discoveries regarding the maintenance and lineage stability versus plasticity of memory Tfh cells will improve strategies that utilize CD4 T cell memory to modulate antibody responses during prime and boost vaccination.

Keywords: Bcl6; CXCR5; T follicular helper cells; helper T cells; memory T cells.

Figure 1

T follicular helper cell differentiation and context-dependent Tfh cell heterogeneity. Following activation of naïve CD4 T cells, cells proliferate and undergo fate decisions in response to cytokines and other differentiating factors. Tfh cell differentiation is influenced by IL-6 and IL-21, and dependent upon ICOS signaling for expression of the transcription factor Bcl6. Cytokines including IL-12, IL-4, IL-1β, and many others, direct (A) Th1, (B) Th2, and (C) Th17 cell differentiation, respectively. The context-dependent cytokine milieu also influences Tfh cell differentiation; thus, Tfh effector cells can express some low/intermediate levels of the transcription factors Tbet, Gata3, and RORγt, which are associated with the (A) Th1, (B) Th2, and (C) Th17 cell lineages, respectively.

Figure 2

Markers of effector and memory Tfh cells. Tfh effector CD4 T cells express high levels of the chemokine receptor CXCR5, the inhibitory receptor PD-1, ICOS, the transcriptional repressor Bcl6, the transcription factor c-Maf, and many other molecules. After antigen clearance, resting memory Tfh cells no longer express Bcl6, ICOS, and IL-21 and many other Tfh associated molecules. Tfh memory cells are characterized by intermediate expression of CXCR5 and other Tfh related molecules and the absence of activation dependent molecules. Bcl6 expression is not detected in memory Tfh cells; however, Maf and other transcription factors are maintained at low/intermediate levels. PD-1 is absent from antigen-specific memory Tfh cells in mice, however, human CXCR5+CXCR3− memory Tfh cells maintain low levels of PD-1 expression that is not dependent on TCR signaling. Folate receptor 4 (FR4), a molecule that is highly expressed on effector Tfh cells, is maintained on CXCR5+ memory Tfh cells.

Figure 3

Models of T helper lineage commitment in memory CD4 T cells. Following activation, naïve CD4 T cells undergo dramatic antigen dependent proliferation to generate effector CD4 T cells. Following antigen clearance, the majority of effector cells undergo apoptosis, leaving behind a pool of antigen-specific memory cells. Upon reinfection or antigen boost, memory cells become reactivated and proliferate, generating secondary effector cells. (A) Potential model for lineage commitment of Tfh memory cells. In this model, antigen-specific CD4 T cells differentiate to become either lineage-committed Tfh cells or lineage-committed effector cells of other lineages (either Th1, Th2, or Th17 depending upon the context of infection or inflammatory stimulus). Resting memory Tfh and non-Tfh cells would maintain their lineage-specific programing, and upon reactivation, would faithfully recall their previously defined T helper lineage phenotype and functions. (B) In this second model, antigen-specific CD4 T cells differentiate toward either Tfh or non-Tfh (Th1, Th2, or Th17) effector cells; however, depending upon the integration of many different stimuli (TCR signals, inflammation, interactions with various antigen-presenting cells, etc.), individual effector cells become transcriptional and epigenetically programed with varying degrees of polarity toward Tfh or non-Tfh cell lineages. Following antigen clearance and T cell contraction, the antigen-specific memory pool is highly heterogenous, being comprised of cells with varying degrees of lineage commitment and T helper lineage-specific recall potential, including highly committed Tfh memory cells, more plastic/pluripotent Tfh and non-Tfh (Th1, Th2, and Th17) memory cells, and highly committed non-Tfh (Th1, Th2, and Th17) memory cells.

Figure 4

Potential mechanisms that promote Tfh recall responses from memory Tfh cells. (A) Differentiated CXCR5+ memory Tfh cells possess cell-intrinsic programs that promote the preferential generation of Tfh secondary effectors cells upon reactivation with antigen. In contrast, uncommitted naïve CD4 T cells are pluripotent, with the capacity to generate a balance of Tfh and non-Tfh (Th1, Th2, Th17) effector cells following activation. (B) The maintenance of Tfh associated transcription factors may promote the recall of the Tfh cell program and inhibit the differentiation of other T helper lineages following activation. The transcription factor Maf, is maintained at low levels in human Tfh memory cells. While Bcl6 expression is not detectable in memory Tfh cells, it is possible that soon after reactivation, rapid reexpression of Bcl6 directs Tfh gene expression as well as inhibits Blimp1 and high expression of Tbet, Gata3, and RORγt. (C) CXCR5 and CCR7 coexpression on memory Tfh cells may provide localization of memory Tfh cells along the T:B cell border either before or early after reactivation, promoting increased interactions with B cells that can reinforce the Tfh cell phenotype and function. In contrast, CCR7+ (CXCR5−) naïve CD4 T cells will become activated in T cells zones by antigen-bearing dendritic cells. (D) Epigenetic programs acquired during Tfh effector differentiation can be maintained in resting memory Tfh cells throughout homeostatic proliferation. Transcriptionally permissive histone modifications and unmethylated DNA at “poised” Tfh associated loci in memory Tfh cells will promote the rapid reexpression of these genes upon reactivation. In addition, repressive histone modifications and DNA methylation will prevent reexpression of Th1, Th2, and Th17-associated genes.