Human blood T _fr cells are indicators of ongoing humoral activity not fully licensed with suppressive function

Abstract

Germinal center (GC) responses are controlled by T follicular helper (T) and T follicular regulatory (T) cells and are crucial for the generation of high-affinity antibodies. Although the biology of human circulating and tissue T cells has been established, the relationship between blood and tissue T cells defined as CXCR5Foxp3 T cells remains elusive. We found that blood T cells are increased in Sjögren syndrome, an autoimmune disease with ongoing GC reactions, especially in patients with high autoantibody titers, as well as in healthy individuals upon influenza vaccination. Although blood T cells correlated with humoral responses, they lack full B cell-suppressive capacity, despite being able to suppress T cell proliferation. Blood T cells have a naïve-like phenotype, although they are absent from human thymus or cord blood. We found that these cells were generated in peripheral lymphoid tissues before T-B interaction, as they are maintained in B cell-deficient patients. Therefore, blood CXCR5Foxp3 T cells in human pathology indicate ongoing humoral activity but are not fully competent circulating T cells.

T follicular regulatory (Tfr) cells: Dissecting the complexity of Tfr‐cell compartments

“…14,47 The depletion of DCs with diphtheria toxin in CD11c-DTR bone marrow chimeric mice also led to reduced levels of Tfr cells, which were rescued by the transfer of NP-OVA-pulsed LPSactivated DCs. 48,50 The circulating Tfr cells appear to maintain lower expression of ICOS and a reduced suppressive capacity, when compared to Tfr cells sorted from lymph nodes. 48,49 However, the DC subsets most directly responsible for stimulating Tfr-cell differentiation remain unclear.…”

“…48 Additionally, antigen presentation by DCs (and not only survival and costimulatory signals) appeared to be required for Tfr-cell differentiation, as Ciita −/− DCs (which are unable to present antigens) were impaired in their ability to induce Tfr-cell differentiation. 48,50 Like Tfh cells, Tfr development requires TCR stimulation and costimulatory signals through CD28 and ICOS. The full differentiation into tissue resident Tfr cells is also dependent on B-cell interactions.…”

“…41 Liu and colleagues showed that Ascl2 retroviral transduction induced CXCR5 in naive CD4 + T cells F I G U R E 2 Human T follicular regulatory (Tfr) cell identification. In B, micrographs were obtained by immunofluorescence microscopy of formalin-fixed paraffin-embedded human tonsils stained for CXCR5 (red), CD4 (green) and DAPI (blue), as described in Fonseca et al 50 in vitro under Treg-cell polarizing conditions. While blood Tfr cells (defined as CXCR5 + Foxp3 + CD4 ++ T cells) are virtually absent prior to mature humoral responses (ie.…”

“…50 Using a comprehensive analysis of different human samples, in health and diseases conditions, we proposed a model in which the acquisition of a CXCR5 + Foxp3 + phenotype by T cells in the tissues precedes access to the follicle, where the cells acquire a fully mature phenotype (Figure 2A). 50 Using a comprehensive analysis of different human samples, in health and diseases conditions, we proposed a model in which the acquisition of a CXCR5 + Foxp3 + phenotype by T cells in the tissues precedes access to the follicle, where the cells acquire a fully mature phenotype (Figure 2A).…”

“…50 Using a comprehensive analysis of different human samples, in health and diseases conditions, we proposed a model in which the acquisition of a CXCR5 + Foxp3 + phenotype by T cells in the tissues precedes access to the follicle, where the cells acquire a fully mature phenotype (Figure 2A). 50 In human blood, Tfr cells do not express PD-1 or Bcl-6 and their ICOS expression did not distinguish these cells from CXCR5 − (conventional) Treg cells. Accordingly, upon commitment to Tfr-cell differentiation (through CXCR5 upregulation), the development of CXCR5 + Treg cells eventually bifurcates toward circulating Tfr cells, in one direction, or toward complete maturation toward tissue resident Tfr cells, in the other direction.…”