T peripheral helper cells in autoimmune diseases: What do we know?

Abstract

The interactions between T cells and B cells are essential for antibody responses and the development of autoimmune diseases. Recently, a distinct subset of T cells capable of helping B cells was established in synovial fluid, and they were termed peripheral helper T (Tph) cells. PD-1^hiCXCR5^-CD4⁺ Tph cells express high levels of CXCL13, which drives the formation of lymphoid aggregates and tertiary lymphoid structures, ultimately facilitating the local production of pathogenic autoantibodies. Tph and T follicular helper cells share some key features but can be distinguished by their surface markers, transcriptional regulation, and migration capability. We summarize recent findings on Tph cells in this review and provide a perspective on their potential roles in a range of autoimmune diseases. More clinical and in-depth mechanistic investigations of Tph cells may help to improve the understanding of pathogenesis and further provide novel therapeutic targets in autoimmune diseases.

Keywords: CXCL13; T follicular helper cells; T peripheral helper cells; autoimmune diseases; tertiary lymphoid structures (TLSs).

Figure 1

Schematic representation of synovial TLSs. Synovial TLSs show striking anatomical similarities to SLOs. Within the lympho-myeloid group of RA patients, TLSs resemble the lymphoid follicles of SLOs, acquiring features such as segregation of T and B cells into separate areas, differentiation of the FDCs networks, development of HEVs, and differentiation of hypermutated and class-switched plasma cells. Tph cells are supposed to be present in the periphery of TLSs, rather than in their center. These crosstalks among Tph, Tfh, Tfr, and B cells regulate the GC response. FDC, follicular dendritic cell; HEV, high endothelial venule. By Figdraw.

Figure 2

B-Tfh cell and B-Tph cell crosstalk. Tfh cells and B cells interact in GCs of SLOs. Bcl6 is a lineage-defining transcription factor of Tfh cells. Tph cells and B cells interact in inflamed tissues. Sox4 is a key transcription factor for CXCL13 production by Tph cells. CCR2 and CCR5 contribute to their recruitment to inflamed tissues. Both Tfh and Tph cells express high levels of IL-21 and CXCL13, which are mandatory for B-cell differentiation. Both Tfh and Tph cells interact with B cells through their respective expression of ICOS, PD-1 and ICOSL, PDL1/2. ICOSL, ICOS ligand; PDL1/2: programmed death-ligand1/2. By Figdraw.