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

Fonseca et al. reported the existence of CD25+ “blood Tfr cells not fully licensed for suppressive function” (1). We and others recently reported that bona fide Tfr do not express CD25 (2-4). This raises the question of the nature of “follicular” cells found outside the follicles.

Blood Tfh-like cells have been described as cells able to promote differentiation and class switch recombination of naïve B cells (5). Not surprisingly given their location, they were found not to express Bcl6. These cells have been named (i) by their phenotype (human blood CXCR5+ T cells (6)), (ii) by their function (the counterpart of T follicular cells (7)), (iii) as “blood Tfh-like cells” (8) cells or more confidently as (iv) “blood Tfh cells” (9). These non-consensual naming denote some unease about qualifying cells with a localization descriptor (i.e. follicular) that does not match their actual localization. Actually, although CXCR5+Bcl6- T cells have a clear B cell helper function, they have not yet been formally traced to a Tfh lineage. Whether they are post- or pre-Tfh cells or independent remains to be demonstrated.

The situation is even more complicated with “blood Tfr” cells, also named “Tfr-phenotype cells in peripheral blood” (10). While “blood Tfh” have a clear B cell helper function in vitro, “blood Tfr” “do not preferentially suppress [the] humoral response” in vitro (1).

As there are no lineage data supporting the concept of “blood Tfr” and “blood Tfh”, we believe that it would be wise to refer to them as Tfr-like and Tfh-like cells until further experiments potentially qualify them as pre- or post-T follicular cells. Alternatively, as there is a consensus for the B cell helper or regulatory function of these cells, it may not be too late to re-qualify these cells as Tbh and Tbr cells, and then to refine this naming with attributes such as those related to their localization, i.e. as blood or follicular cells. Perhaps the timing is right for a consensus meeting on the matter.

References
1. V. R. Fonseca et al., Human blood Tfr cells are indicators of ongoing humoral activity not fully licensed with suppressive function. Sci. Immunol. 2 (2017), doi:10.1126/sciimmunol.aan1487.
2. P.-G. G. Ritvo et al., Tfr cells lack IL-2Rα but express decoy IL-1R2 and IL-1Ra and suppress the IL-1–dependent activation of Tfh cells. Sci. Immunol. 2, eaan0368 (2017).
3. J. B. Wing et al., A distinct subpopulation of CD25− T-follicular regulatory cells localizes in the germinal centers. Proc. Natl. Acad. Sci., 201705551 (2017).
4. D. Botta et al., Dynamic regulation of T follicular regulatory cell responses by interleukin 2 during influenza infection. Nat. Immunol. advance online publication (2017), doi:10.1038/ni.3837.
5. N. Schmitt, S.-E. Bentebibel, H. Ueno, Phenotype and Functions of Memory Tfh cells in Human Blood. Trends Immunol. 35, 436–442 (2014).
6. R. Morita et al., Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity. 34, 108–121 (2011).
7. M. Locci et al., Human Circulating PD-1+CXCR3−CXCR5+ Memory Tfh Cells Are Highly Functional and Correlate with Broadly Neutralizing HIV Antibody Responses. Immunity. 39, 758–769 (2013).
8. N. Schmitt, H. Ueno, Blood Tfh Cells Come with Colors. Immunity. 39, 629–630 (2013).
9. J. S. Hale et al., Distinct memory CD4+ T cells with commitment to T follicular helper- and T helper 1-cell lineages are generated after acute viral infection. Immunity. 38, 805–817 (2013).
10. C. Jandl et al., IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2. Nat. Commun. 8, 14647 (2017).