Indexation as a Novel Mechanism of Lymphocyte Homeostasis: The Number of CD4+CD25+ Regulatory T Cells Is Indexed to the Number of IL-2-Producing Cells

Abstract

To fulfill its mission, the immune system must maintain a complete set of different cellular subpopulations that play specific roles in immune responses. We have investigated the mechanisms regulating CD4+CD25+ regulatory T (Treg) cell homeostasis. We show that the expression of the high-affinity IL-2Rα endows these cells with the capacity to explore the IL-2 resource, ensuring their presence while keeping their number tied to the number of CD4+ T cells that produce IL-2. We show that such a homeostatic mechanism allows the increased expansion of T cells without causing disease. The indexing of Treg cells to the number of activated IL-2-producing cells may constitute a feedback mechanism that controls T cell expansion during immune responses, thus preventing autoimmune or lymphoproliferative diseases. The present study highlights that maintenance of proportions between different lymphocyte subsets may also be critical for the immune system and are under strict homeostatic control.

Agonist-Driven Development of CD4+CD25+Foxp3+ Regulatory T Cells Requires a Second Signal Mediated by Stat6

“…Five weeks after adoptive T cell transfer, we found that upon in vivo Ag stimulation Ag-specific STAT6 Ϫ/Ϫ out-competed STAT4 Ϫ/Ϫ CD4 ϩ T cells (data not shown) as it was the case during LDP of polyclonal T cells (9). More importantly, we found that the fraction of Treg cells recovered after adoptive transfer of WT, STAT4 Ϫ/Ϫ , or STAT6 Ϫ/Ϫ TCR-HA CD4 ϩ T cells was Ͻ2% and identical in both Ag-free and HA ϩ hosts (data not shown) and indistinguishable from that of the original injected CD4 ϩ T cell population (13). This indicates that the exposure of mature peripheral HA-specific T cells to HA did not result in "de novo" generation of Foxp3 ϩ Treg cells, in contrast to what was observed when these cells developed throughout the thymus of the HA BM chimeras (see Fig.…”

“…In the peripheral compartments of the HA-free BM chimeras, the number of Ag-specific CD4 ϩ 6.5 ϩ T cells was similar (range from 2.9 to 3.6 ϫ 10 6 ) whether the mice were reconstituted with WT, STAT4-, or STAT6-deficient TCR-HA BM (Fig. 1b), indicating that peripheral homeostatic mechanisms operate to compensate the lower SP compartment of the STAT-deficient HA-specific T cells (13). In the BM chimeras expressing HA, the number of peripheral CD4 ϩ 6.5 ϩ T cells was reduced as compared with HA-free chimeras (12).…”

“…In humans STAT5b is also important for the in vivo accumulation of Treg cells (20) and it was recently shown that in vitro IL-2 up-regulates Foxp3 expression through a STAT5-dependent mechanism (21). However, most of the available data suggest that IL-2 signals are not essential for the generation of Treg cells, but rather to their peripheral survival and expansion (13,22,23). Indeed, CD4 ϩ CD25 ϩ Foxp3 ϩ cells are strongly reduced, but not totally absent in either IL-2-or STAT5-deficient mice (19,22).…”

“…Whether, in the absence of IL-2, STAT6 acts in association or independently of STAT5 remains to be established. In contrast, at the periphery, survival of functional Treg cells has been shown to be strictly dependent on IL-2 levels (13,35). Thus, in Stat6VT mice the constitutive STAT6 activation, which relatively enriches the peripheral CD4 ϩ T cell pool with cells of the Foxp3 ϩ Treg lineage, probably favors Treg cell survival by using common downstream elements of the IL-2 pathway.…”

CD4+ T Cells from Simian Immunodeficiency Virus Disease-Resistant Sooty Mangabeys Produce More IL-2 Than Cells from Disease-Susceptible Species: Involvement of p300 and CREB at the Proximal IL-2 Promoter in IL-2 Up-Regulation

“…Our recent data do not suggest the presence of higher frequencies of regulatory T cells (CD25 high /FOXP3 ϩ ) in mangabeys (52). Low, but consistent IL-2 levels detected in SM may, however, potentiate their function (17,50,51) and limit the activation of effector T cells, therefore limiting immunopathology associated with chronic high viremia infection such as HIV or SIV. This mechanism is being addressed in ongoing studies.…”