T follicular helper cell diversity and plasticity

Abstract

CD4(+) T helper (Th) cells play an instrumental role in orchestrating adaptive immune responses to invading pathogens through their ability to differentiate into specialized effector subsets. Part of this customized response requires the development of T follicular helper (Tfh) cells, which provide help to B cells for the generation of germinal centers (GCs) and long-term protective humoral responses. Although initially viewed as terminally differentiated, we now recognize that Th cell subsets, including Tfh cells, display substantial flexibility and overlap in their characteristics. In this review, we highlight advances in our understanding of Tfh cell development, cytokine production, and the potential plasticity that allows Tfh cells to possess characteristics of other effector Th cell populations.

Figure 1

Flexibility and plasticity of Tfh cells. Tfh cells express a constellation of transcription factors required for development including Bcl-6, BATF, STAT3, IRF4 and c-Maf, many of which are expressed by other Th effector subsets (indicated in the overlap of the cells). Tfh cells can also express transcription factors and Th effector cytokines (Gata-3 for IL-4 and T-bet for IFN-γ) depending on nature of stimulation. Although Th cell subsets express distinct transcription factors, epigenetic analysis has revealed that chromatin modifications may allow flexibility in the expression of ‘master regulator’ transcription factors (H3K4me3 modifications indicative of permissive active chromatin are indicated). Thus, rather than transcription factor expression viewed as ‘all or none’ it may be important to consider the balance of transcription factors expressed. This is likely advantageous for host defense, as both Th effectors and Tfh cell-driven B cell responses are often required for effective pathogen clearance.

Figure 2

Multiple CD4⁺ T cell populations can adopt Tfh characteristics. Foxp3⁺ T regulatory cells and NKT cells can express markers consistent with Tfh cell populations. During immunization with lipid antigen, a subset of NKT cells can express Tfh cell markers and provide B cell help. However, NKTfh cells are not able to induce memory B cell formation and long-lived plasma cells (indicated by the dotted line). Following protein immunization, Foxp3⁺ Tregs can increase expression of the transcription factor Bcl-6 and express CXCR5, and migrate into the GC where these cells can regulate the GC response. Additionally, Foxp3⁺ cells found within the intestine, can also upregulate Tfh markers and reduce Foxp3 expression, migrate into the B cell follicle of Peyer’s Patches and function as bone fide Tfh cells.

Figure 3

Diversity of Tfh cells. Tfh cells can further specialize through upregulation or activation of transcription factors in response to different environmental stimuli. For example, during a helminth infection, Tfh cells can express the transcription factor Gata-3 and express IL-4. However, Th2 effector cells preferentially found in peripheral sites express higher levels of Gata-3 (Gata-3 gradient: Th2>Tfh2>Tfh) and produce IL-4 as well as other effector cytokines including IL-13. Thus, we propose a model whereby CD4⁺ T cells may receive pathogen and milieu specific signals to induce different levels of expression of Th cell subset specific transcription factors, enabling a customized response critical for the development of protective humoral immunity. This model would suggest that Tfh cells are not terminally differentiated, but retain the ability to acquire characteristics of other Th cell subsets upon subsequent challenge.