Follicular T Helper Cells - What They Are and How PD-1 Regulates Them

As its name suggests, follicular T helper cells (Tfhs) are a subset of activated T cells that specialize in providing T cell help to corresponding B cells. They play a critical role in regulating the formation of germinal center (GC) and the subsequent cellular reactions. With the aid and management from these Tfhs, B cells are able to properly proliferate and mutate somatically to render most high affinity antibodies and memory B cells1. Tfhs are most commonly found in the periphery within B cell follicles and they constitutively express B cell follicle homing receptor C-X-C chemokine receptor type 5 (CXCR5).

A wide spectra of the functions and relevance have been reported including the generation of lasting immune memory, the control of age-related immune declination, the avoidance of autoimmunity, and most recently, the elicited vaccine immune responses2. Diseases such as chronic lymphocyte choriomeningitis virus (CLMV) infection and simian immunodeficiency virus (SIV, a similar immunodeficiency disease to HIV) infection are closely associated with Tfhs as they are vital for the production of the matured antibodies for protective response to these viruses.

While the regulations of Tfhs are largely remain unsolved, it has been widely recognized that Tfh cell development is modulated by a cascade of transcriptional factors with the primary one being B cell lymphoma 6 (BCL-6). Antigen activation triggers the up-regulation of BCL-6 together with inducible T cell co-stimulator (ICOS) which in turn direct activated T cells to relocate and enter the follicles. Recently, Hai Qi and colleagues proposed a new mechanism in PD-1 regulation of the activated helper T cells3. In what they call a “bystander mode”, a group of bystander B cells regulate follicular T cell recruitment with the aid from ICOS and PD-L1. As their study shows, when the bystander B cells that constitutively expressing PD-L1 are working in accordance as an effector complex, PD-1 has demonstrated inhibitory effect that hinders the movement of T cells into the follicle. PD-1 also restricts the cellular mechanism that locally concentrate the Tfh cells in the GC area that facilitates the B cell competition and maturation.

Reference

• Crotty, S., 2015. T follicular helper cell differentiation, function, and roles in disease. Cell Immunity, 41(4): 529-542. DOI: 10.1016/j.immuni.2014.10.004.
• Qi, H. 2016. T follicular helper cells in space-time, Nature Reviews Immunology, 16(10):612-25. DOI: 10.1038/nri.2016.94.
• Shi J., Qi, H., 2018. PD-1 Controls Follicular T Helper Cell Positioning and Function, Cell Immunity, 49, 264-274, DOI: 10.1016/j.immuni.2018.06.012