Is IL-7 from dendritic cells essential for the homeostasis of CD4+ T cells?
In a recent article in Nature Immunology 1, Guimond et al. offered an interesting explanation for why naïve CD4+ T cells undergo slower IL-7-driven homeostatic proliferation than CD8+ T cells (ref. 1, 2. and Supplementary Fig. 1). Guimond et al. concluded that CD4+ T cells can respond efficiently to IL-7, but only when IL-7 is expressed selectively on dendritic cells (DC) and not on stromal cells, the main producers of IL-7 for homeostasis of naïve T cells 3, 4. As evidence, Guimond et al. showed several sets of correlative data, but their direct proof was the finding that polyclonal and Marilyn TCR transgenic CD4+ T cells proliferated strongly in bone marrow (BM) chimeras where IL-7 was expressed only by BM-derived and not by stromal cells (IL-7+ BM ? IL-7?/? chimeras). However, we were troubled that the rate of CD4+ T cell expansion in these chimeras was 50-100-fold higher than for typical IL-7-driven homeostatic proliferation in wild-type lymphopenic hosts. For polyclonal T cells, there is the caveat that a fraction of these cells respond strongly to environmental and commensal microflora antigens in the lymphopenic hosts5-7 (Supplementary Fig 1). This concern does not apply to Marilyn cells and most other CD4+ TCR transgenic lines, which undergo minimal proliferation in lymphopenic hosts 2, 8. Therefore, we checked proliferation of SMARTA transgenic CD4+ cells. However, in striking contrast to Marilyn cells, SMARTA cells failed to undergo any detectable proliferation in IL-7+ BM ? IL-7?/? chimeras (Supplementary Fig. 1). Unlike SMARTA cells, Marilyn cells are specific for mouse male HY antigen, and undergo intense proliferation in male, but not in female, hosts (Fig. 1A). Since Guimond et al. did not specify that their BM chimeras were generated using only female mice, we tested whether female chimeras would still support intense proliferation of Marilyn cells. Here, the striking finding was that proliferation of Marilyn cells in female IL-7+ BM ? female IL-7?/? chimeras was virtually undetectable (Fig. 1A). In contrast, as expected, male IL-7+ BM ? female IL-7?/? chimeras supported massive proliferation of donor Marilyn cells (Fig. 1A). These results suggest that the prominent expansion of Marilyn cells reported by Guimond et al. was not due to IL-7 expressed by the BM-derived cells, but instead reflected an immune response to contaminating male cells in their chimeras. In a related experiment Guimond et al. showed that Marilyn cells undergo a faster rate of homeostatic proliferation in female lymphopenic IL-7R?/? hosts than in RAG?/? hosts, a finding which we confirm (Fig. 1B). While Guimond et al. interpret this to indicate that signaling through IL-7R on APC inhibits homeostasis of CD4+ T cells, further analysis suggests otherwise. Notably, we find that IL-7R?/? hosts support enhanced homeostatic proliferation not only of CD4+ T cells but also of polyclonal and TCR transgenic CD8+ T cells (Fig. 1C). Therefore, the simplest explanation for these findings is that the strong homeostatic proliferation of T cells in IL-7R?/? mice reflects merely a higher concentration of IL-7 in these mice than in normal IL-7R+ lymphopenic hosts. In summary, our current findings with gender-matched BM chimeras, SMARTA cells and IL-7R?/? hosts collectively cast serious doubt on the validity of the central conclusions reached by Guimond et al.
|Authors||Martin, C. E.; Kim, D. M.; Sprent, J.; Surh, C. D.:|
|Publisher Name||NAT IMMUNOL|
|Published Date||2010-06-19 00:00:00|
|Published Pages||547-8; author reply 548|
|OpenAccess Link||https://publications.gimr.garvan.org.au/download.php?10662_11012/10 Martin ni0710-547_.pdf|