In a recent article, Dorfman et al.1 investigated whether basal T cell receptor (TCR)ζ chain phosphorylation depends on TCR interaction with self–major histocompatibility complex (MHC) molecules. Although these data are interesting in the context of peripheral T cell survival, the authors concluded differently and ended up stating that lymphocyte survival is not dependent on self-MHC expression. This was because in their experiments donor CD4+ T cell numbers declined in both normal and class II MHC–deficient (Aβ-KO) recipients. These conclusions are in marked contrast to those of previous reports2,3,4,5,6,7, which addressed the same question but in different experimental systems. However, the inability of Dorfman et al.1 to determine an influence of peripheral self-MHC on CD4+ T cell survival might be explained by the inappropriate experimental system they used.

Peripheral T cell pool sizes are limited by, as yet, unknown factors (ref. 8 and references therein). Dorfman et al. compared lymphocyte survival after transfer into normal and Aβ-KO mice. This is not appropriate because in the latter case donor CD4+ T cells do not have to compete with recipient cells, whereas in the former case they have to compete with a full preformed pool of host CD4+ cells. In addition, the continuous thymic output of CD4+ T cells in normal mice (but not Aβ-KO mice) will gradually replace peripheral CD4+ T cells, including those derived from the donor, as is the case for CD8+ T cells9. For these reasons, normal mice cannot be used as controls for experiments with Aβ-KO mice. It is like comparing apples to oranges.

The authors observed proliferation of donor CD4+ T cells in Aβ-KO recipients. Proliferation ceased once the mice were infused with antibodies to class II MHC, which indicated the presence of residual class II MHC on host- or donor-derived cells. Regardless of the cell type, the antibody-blocking studies were performed to exclude the contact of CD4+ T cells with (residual) self-MHC. Although the antibodies were sufficient to block proliferation of donor CD4+ T cells in Aβ-KO recipients, we do not know whether the dose was adequate to block the contact to self-MHC that is required for CD4+ T cell survival. This is because proliferation could well require stronger stimuli than those needed for survival10 and, thus, would result in a slower decline of CD4+ T cells. Here, it is irrelevant that the authors observed an immediate down-regulation of TCRζ chain phosphorylation when blocking self-MHC because we do not know how much phosphorylation is required for survival. The differing kinetics between T cell survival in the absence of self-MHC (t1/2 of approximately three weeks2,5,7, J. Kirberg, unpublished data) and diminished TCRζ chain phosphorylation (within 36 h), as seen by Dorfman et al.1, might suggest that this is actually the case.

In summary, the similar decline of CD4+ T cells in the different mice may occur for very different reasons in the experiments by Dorfman et al.1: competition and replacement in normal recipients and death due to the absence of TCR contact with self-MHC molecules in Aβ-KO recipients. We find no basis to interpret the data as Dorfman et al.1 have, questioning the concept of TCR “tickling” by self-MHC as a prerequisite for peripheral survival. Finally, basic TCRζ chain phosphorylation might still mediate survival downstream of the TCR “tickling” but this cannot be concluded from the data either.

See Response to 'Class II essential for CD4 survival' by Jeffrey R. Dorfman and the Concentration of MHC class II molecules in lipid rafts facilitates antigen presentation by Jeffrey R. Dorfman.