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

Hiroyuki Yoshitomi,Hideki Ueno

doi:10.1038/s41423-020-00529-z

Hiroyuki Yoshitomi, Hideki Ueno

Open Access

https://doi.org/10.1038/s41423-020-00529-z

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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.

Highlights

In the 1980s, CD4+ “helper” T cells were initially defined as T cells capable of providing help to B cells.[1]
During the past two decades, T follicular helper (Tfh) cells have been established as a CD4+ subset that is specialized to provide help to B cells in the germinal centers of secondary lymphoid organs (SLOs)
CD4+ T cells within tertiary lymphoid structures (TLSs) share many features with Tfh cells, including the expression of CXCL13, IL-21, CD40L, and ICOS, but often lack expression of the chemokine receptor CXCR5.15 A series of studies on CD4+ T cells in inflamed rheumatoid arthritis (RA) joints demonstrated the presence of CXCL13-producing PD-1hi CXCR5−CD4+ T cells that were capable of helping B cells within inflamed tissues,[16,17] and these CD4+ T cells were termed peripheral helper T (Tph) cells.[15]