Helper T cells seek long-term partner

During the course of an immune response, antigen-specific CD4⁺ T helper (T_H) cells are known to pair up first with dendritic cells (DCs) and later with B cells. But now, a third, longer-term partner for T_H cells has been described.

In confocal microscopy studies of mouse spleens, Kim et al. uncovered a new population of CD4⁺ cells, which are not T cells (as they are CD3⁻) or classical DCs (as they are CD11c⁻). In contrast to DCs, which are found in the T-cell zones, these CD3⁻CD4⁺ cells are located mainly in B-cell follicles and at the interface between T-cell and B-cell areas — sites where T cells and B cells are known to collaborate.

To investigate the potential involvement of these cells in an immune response, T-cell receptor (TCR)-transgenic CD4⁺ T cells were transferred into normal mice, which were then immunized. Soon after immunization (day 2), most of the antigen-specific T cells were associated with DCs, but by day 5, a shift in favour of interactions with CD3⁻CD4⁺ cells was evident.

In contrast to the DCs in the T-cell zone, the CD3⁻CD4⁺ cells expressed low levels of MHC class II molecules and the co-stimulatory molecules CD40, CD80 and CD86, but they expressed high levels of the tumour-necrosis factor family members OX40L and CD30L. This was intriguing as OX40 and CD30 are expressed by T cells and have been described to have co-stimulatory functions. The authors found that CD3⁻CD4⁺ cells potentiate the survival of T_H2 cells — which preferentially express OX40 and CD30 — but not T_H1 cells in vitro, an effect that seems to depend partially on signals from OX40. Moreover, OX40-expressing TCR-transgenic T cells had a clear survival advantage over OX40-deficient cells when they were co-transferred into mice that were immunized with a T_H2-cell polarizing antigen, with most OX40⁺ T cells associating with CD3⁻CD4⁺ cells. Further in vivo studies showed that the duration of antibody responses and T_H-cell memory are impaired in the absence of OX40 signals.

So, drawing the evidence together, it seems that OX40 signals from this new type of accessory cell might be essential for maintaining T_H cells at the sites of T-cell–B-cell interaction in the later phases of antibody responses.