Where you are is what you are

Comment on Hardtke et al, page 1924

In this issue, Hardtke and colleagues conclusively demonstrate that expression on T cells of the B-cell–associated chemokine receptor, CXCR5, is essential for migration into B follicles (follicular B helper T cells [T_FH]) and, further, that T cells are excluded from B follicles by the T cells' expression of the T-zone–associated chemokine, CCR7.

Band T cells are normally segregated within lymphoid tissue by chemokine gradients that are established by local populations of lymphoid stromal cells. CXCR5⁺ B cells are attracted to the areas forming B follicles, whereas both CCR7⁺ T cells and antigen-presenting dendritic cells are attracted to sites that form T zones. This isolation of B cells from T-cell areas is essential for the production of high-affinity antibodies, as it excludes T cells of irrelevant specificities from the B follicle in which B-cell selection by “licensed” T_FH occurs.

As others have found,¹  induction of CXCR5 on T cells occurs rapidly following priming and identifies cells destined to provide help in B follicles but not inflammatory responses. Although CXCR5 is expressed on a substantial fraction of primed T cells, many such cells continue to coexpress CCR7, an expression motif that localizes them at the B–T interface where the chemokine gradients establishing the B follicle and T zone compete for influence. Since activated CXCR5-expressing B cells mirror the situation in T cells by up-regulating CCR7,²  they too localize at the B–T interface, an arrangement likely to optimize the efficiency of B–T collaboration not only for primary antibody production but also for memory responses. Only a minority of CXCR5⁺CCR7⁺-expressing T cells go on to down-regulate CCR7 and become mature T_FH where they foster the development of B-cell germinal centers, the structures within which affinity maturation of the B-cell response occurs. It is not certain which signals induce T cells to do this; perhaps the signals arise from some as-yet-unidentified interaction with antigen-activated B cells.

One very interesting observation from Hardtke et al is that dual CXCR5⁺CCR7⁺-expressing T cells appear in lymph nodes where there is no obvious ongoing B-cell response (see figure), suggesting that these T cells might have migrated there following priming elsewhere. This possibility is supported by the fact that these T cells are found in blood.³  I think that these are recirculating memory cells primed to provide B-cell help and that their dual expression of CXCR5⁺CCR7⁺ guides them to a CD4⁺CD3^- non–dendritic cell located at the B–T interface.⁴  My colleagues and I have found that the development and persistence of T memory cells that provide help to B cells depend on OX40 (CD134) and CD30 survival signals from these cells.⁵  The location of the T memory cells at the B–T interface puts them in pole position to provide rapid help to B cells at the earliest sign of reinfection, but the theory remains to be tested. ▪