Shared and distinct roles of T peripheral helper and T follicular helper cells in human diseases

Abstract

The interactions of CD4⁺ T cells and B cells are fundamental for the generation of protective antibody responses, as well as for the development of harmful autoimmune diseases. Recent studies of human tissues and blood samples have established a new subset of CD4⁺ B helper T cells named peripheral helper T (Tph) cells. Unlike T follicular helper (Tfh) cells, which interact with B cells within lymphoid organs, Tph cells provide help to B cells within inflamed tissues. Tph cells share many B helper-associated functions with Tfh cells and induce B cell differentiation toward antibody-producing cells. The differentiation mechanism is also partly shared between Tph and Tfh cells in humans, and both Tfh and Tph cells can be found within the same tissues, including cancer tissues. However, Tph cells display features distinct from those of Tfh cells, such as the expression of chemokine receptors associated with Tph cell localization within inflamed tissues and a low Bcl-6/Blimp1 ratio. Unlike that of Tfh cells, current evidence shows that the target of Tph cells is limited to memory B cells. In this review, we first summarize recent findings on human Tph cells and discuss how Tph and Tfh cells play shared and distinct roles in human diseases.

Keywords: CXCL13, Autoantibodies; T follicular helper cells; autoimmune diseases; peripheral helper T cells.

Fig. 1

Differentiation of Tfh and Tph cells in humans. Smad2 and Smad3 activation by TGF−β and Activin A is vital for the differentiation of naïve CD4⁺ T cells into Tfh and Tph cells. Environmental IL-2 inhibits the differentiation of both subsets. Activated Stat3 and Stat4 induced by IL-12 and IL-23 stimulation promotes the development of CXCR5⁺ Tfh precursors that migrate toward B cell follicles and eventually differentiate into Bcl-6^hi mature Tfh cells. CXCR5⁻ non-Tfh cells exit the secondary lymphoid organs and migrate into peripheral inflamed tissues under the direction of chemokine receptors (CCR2, CCR5, CXCR3, CX3CR1, etc.). TGF−β stimulation contributes to the production of CXCL13 by Tph-like cells via Sox4 and, as such, to the formation of tertiary lymphoid structures (TLSs) in inflamed tissues. Both Bcl-6 and Sox4 likely contribute to CXCL13 expression by Tfh cells. Tph-like cells might gain Th1 and Tfh-like features in inflamed tissues in response to environmental cytokines, including IL-12, IL-23, IL-6, and type I IFN, in the inflamed tissues. Alternatively, Tfh and Tph cells might coevolve in inflamed lymphoid organs in response to Tfh-promoting cytokines, and Tph precursors differentiate into mature Tph cells in the periphery. In TLSs, Tph cells can localize outside lymphoid follicles (extrafollicles) and provide help to memory B cells. CXCR5⁻ atypical memory B cells might also be a target of Tph cells. The transcription factor Maf is integral for IL-21 expression in both Tph and Tfh cells