Ontogeny, function, and peripheral homeostasis of regulatory T cells in the absence of interleukin-7

Abstract

Mice lacking interleukin-7 (IL-7 ؊/؊ mice) have no signs of autoimmune disease, contrary to other models of lymphopenia. We investigated whether the absence of disease was due to the fact that IL-7 is dispensable for the ontogeny, function, and homeostasis of regulatory CD4 ؉ T cells. We show here that the establishment of the peripheral pool of IntroductionIn healthy individuals, the number of peripheral T lymphocytes is tightly regulated and remains stable throughout life. The mechanisms responsible for this homeostatic control of T-cell numbers are multiple and not yet entirely understood. Survival, expansion, and death of lymphocytes are dependent on both cell-mediated signals and cell-mediated cytokines (for a review, see Freitas and Rocha 1 ). Among the latter, ␥ chain-dependent cytokines are involved in the development and homeostasis of both naive 2,3 and memory T-cell pools. 4,5 In particular, the lifespan of naive T cells is drastically reduced in the absence of 6,7 and this interleukin is involved in the generation and survival of memory CD4 ϩ T cells. 8 IL-7 is produced by bone marrow and thymic stromal cells and is essential for murine T and B lymphopoiesis. 9,10 The thymic cellularity of IL-7 Ϫ/Ϫ mice is drastically reduced (20-fold) due to a blockage at the DN2 to DN3 transition, 11 although the distribution of the major thymocyte subsets is normal. 9 In the periphery, the number of splenic T and B cells is 10-and 20-fold reduced, respectively, compared with wild-type animals. 9 It is known that severe lymphopenia can be associated with lymphoproliferation of both naive and memory T cells. 2,12,13 Lymphopenia can also lead to immune dysregulation resulting in autoimmune disorders 14,15 and other inflammatory diseases (eg, inflammatory bowel disease [IBD]). 16,17 It is also well documented that in some such cases, disease is due to a deficit in numbers or in the function of natural regulatory Foxp3-expressing CD4 ϩ CD25 ϩ T cells. 18 This specialized subset of lymphocytes is essential for the maintenance of peripheral tolerance to self antigen, 19,20 in the regulation of adaptative 21,22 and innate immune response against pathogens 23 and in the control of peripheral lymphocyte numbers. 24 Despite severe lymphopenia, IL-7 Ϫ/Ϫ mice are healthy and display no overt signs of autoimmune disease. One possible explanation is that IL-7 is dispensable for the development, homeostasis, and function of regulatory Foxp3-expressing CD4 ϩ T cells. Another, nonexclusive possibility is that IL-7 is required for the development of efficient immune responses.We show here that the development and the establishment of the peripheral pool of Foxp3-expressing regulatory CD4 ϩ T cells is IL-7 independent. In spite of lymphopenia and early thymic involution, the size of the splenic CD4 ϩ T-cell compartment and the relative frequency of Foxp3-expressing CD4 ϩ CD25 ϩ T cells remain constant up to 28 weeks of age. At this time point essentially all CD4 ϩ T cells are activated in both the CD25 Ϫ and the CD25 ϩ compartments....

Development of regulatory T cells requires IL-7Rα stimulation by IL-7 or TSLP

“…92 Thus, deletion of IL-7 (or IL-7R␣) results in loss of pro-T2 and -T3 cells 93,94 and the majority of ␣␤T cells that descend from them. Our results show that Treg cell development is relatively normal in the absence of IL-7 itself, verifying the findings of Peffault de Latour 60 ) and suggesting that unlike the majority of ␣␤T cells, Treg cells may not develop from typical IL-7-dependent pro-T2 and -T3 cells. This adds to the previously noted distinctive characteristics of thymic Treg cells.…”

“…by guest www.bloodjournal.org From in Treg development indicates another important role for TSLP beyond its importance in mediating inflammatory processes such as allergic inflammation in the lung and atopic skin diseases. [73][74][75][76][77] We verified the report 60 that, unlike other subsets of T cells, Treg cells developed relatively normally in IL-7 Ϫ/Ϫ mice, suggesting that the IL-7 receptor is activated by more than one ligand during Treg cell development and implicating TSLP. Of the 2 ligands, Treg cell progenitors may somewhat favor IL-7 over TSLP, since anti-IL-7 treatment reduces Treg cells in mice that have TSLPR (Figure 5), although as we have emphasized, this effect is stronger in mice lacking TSLPR.…”

“…One explanation is that a month of anti-IL-7 treatment partially inhibits thymic Treg generation in the adult mouse thymus ( Figure 5), which in turn inhibits seeding of peripheral Tregs. Although IL-7 Ϫ/Ϫ mice had substantial numbers of Treg cells in our experiments (Figure 1D), the study of de Latour 60 reported an overall reduction in Tregs in IL-7 Ϫ/Ϫ mice, although the reduction was less severe than other T-cell subsets.…”

“…It was previously reported that Treg cells are independent of IL-7, 60 and human Treg cells express low levels of IL-7R␣, 61 distinguishing them from most other major subsets of T cells that require IL-7 during thymic development and in the periphery. Here we show that in IL-7R␣ Ϫ/Ϫ mice, Treg cells do not develop in the thymus and are absent in peripheral lymphoid organs.…”

“…40 The Tr1 cell, another type of suppressor cell that acts by secreting suppressive cytokines, has been shown to respond to IL-7 in vitro. 59 It has recently been reported that Treg cells develop, survive, and function normally in mice that lack IL-7, 60 suggesting the Treg cell lineage has requirements quite different from the major lineages of T cells, all of which require IL-7. Moreover, a recent study in human Treg cells noted that IL-7R␣ chain is expressed at much lower levels than on other T-cell subsets and suggested that this low expression is a useful marker for distinguishing Treg cells.…”