Sa.117. Gut-Homing CD4+ Lymphocytes are Specifically Targeted in Cynomolgus Monkeys Dosed with Anti-Beta7 Antibody (original) (raw)
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A Function for IL-7R for CD4+CD25+Foxp3+ T Regulatory Cells
The Journal of Immunology, 2008
The IL-2/IL-2R interaction is important for development and peripheral homeostasis of T regulatory (Treg) cells. IL-2- and IL-2R-deficient mice are not completely devoid of Foxp3+ cells, but rather lack population of mature CD4+CD25+Foxp3high Treg cells and contain few immature CD4+CD25−Foxp3low T cells. Interestingly, common γ chain (γc) knockout mice have been shown to have a near complete absence of Foxp3+ Treg cells, including the immature CD25−Foxp3low subset. Therefore, other γc-cytokine(s) must be critically important during thymic development of CD4+CD25+Foxp3+ Treg cells apart from the IL-2. The present study was undertaken to determine whether the γc-cytokines IL-7 or IL-15 normally contribute to expression of Foxp3 and Treg cell production. These studies revealed that mice double deficient in IL-2Rβ and IL-7Rα contained a striking lack in the CD4+Foxp3+ population and the Treg cell defect recapitulated the γc knockout mice. In the absence of IL-7R signaling, IL-15/IL-15R ...
Journal of Leukocyte Biology, 2008
IL-2 is essential for CD4؉CD25؉ forkhead box P3؉ (FoxP3؉) naturally occurring regulatory T cell (Treg) homeostasis and activation. Binding of IL-2 to its receptor leads to phosphorylation of STAT5, and binding of phosphorylated STAT5 to the foxp3 promoter increases foxp3 transcription, resulting in elevated levels of FoxP3 protein in Tregs. Transcriptional regulation by the elevated levels of FoxP3 is thought to be essential for the strong suppressor function seen in activated Tregs. IL-2 belongs to a family cytokines, which all depend on the common ␥-receptor chain (␥c). Given the well-documented effects of IL-2 on Treg function, the effect of other IL-2 family cytokines (IL-7, -15, and -21) on Tregs was examined. We observed that IL-7 and IL-15 induce STAT5 phosphorylation and up-regulation of FoxP3 in Tregs. STAT5 activation correlated with enhanced viability. However, only in the presence of IL-2 did Tregs acquire potent suppressor function. This finding is surprising, as IL-15 as well as IL-2 use the same IL-2R c and ␥c for signaling. In contrast, IL-21 activated STAT3 but did not activate STAT5 and had no effect on Treg viability, activation, or function. We therefore conclude that phosphorylation of STAT5, mediated through the IL-2R␥, promotes Treg survival in a resting and activated state. However, activation of STAT5 alone in conjunction with TCR signaling is not sufficient for the induction of potent suppressor function in Tregs, as IL-7 and IL-15 are not capable of inducing potent Treg suppressor function. J. Leukoc. Biol. 84: 973-980; 2008.
Cellular & Molecular Immunology, 2014
Regulatory T (Treg) cells play a critical role in the maintenance of tolerance. B-1a cells belong to a specific and functionally important B-cell subset that exerts its regulatory role through the production of IL-10. While IL-10 has been correlated with the induction of type 1 Treg (Tr1) cells or Tr1-like cells, whether IL-10-producing B-1a cells are able to induce Treg cells, especially the Tr1 lineage, is poorly understood. We have demonstrated that, similar to the reported B-2 cells, B-1a cells are able to convert naïve CD4 1 CD25 2 T cells into a subset of T cells with suppressive function, which we called 'Treg-of-B1a' cells. Treg-of-B1a cells do not express Foxp3, but upregulate the Treg markers OX40, programmed death 1 (PD-1), inducible costimulator (ICOS) and IL-10R. Moreover, Treg-of-B1a cells do not express Foxp3 and produce high levels of IFN-c and IL-10, but minimal amounts of IL-4; therefore, they resemble Tr1 cells. However, utilizing IL-10 2/2 mice, we showed that IL-10 was not involved in the induction of Treg-of-B1a cells. On the contrary, CD86-mediated costimulation was essential for B-1a cells to drive the induction of Treg-of-B1a cells. Finally, we demonstrated that, in contrast to the Treg cells generated by B-2 cells that mediate contact-dependent suppression, Treg-of-B1a cells suppress through secreting soluble factors. While Tr1 cells mediate suppression mainly through IL-10 or TGF-b secretion, Treg-of-B1a cells mediate suppression through an IL-10-and TGF-b-independent pathway. Together, these findings suggest that B-1a cells induce a functionally and phenotypically distinct Treg population that is dissimilar to the reported Foxp3 1 Treg or Tr1 cells.
CD4 blockade directly inhibits mouse and human CD4+ T cell functions independent of Foxp3+ Tregs
Journal of Autoimmunity, 2013
a b s t r a c t CD4 þ helper T cells orchestrate protective immunity against pathogens, yet can also induce undesired pathologies including allergies, transplant rejection and autoimmunity. Non-depleting CD4-specific antibodies such as clone YTS177.9 were found to promote long-lasting T cell tolerance in animal models. Thus, CD4 blockade could represent a promising therapeutic approach for human autoimmune diseases. However, the mechanisms underlying anti-CD4-induced tolerance are incompletely resolved. Particularly, multiple immune cells express CD4 including Foxp3 þ regulatory T cells (Tregs) and dendritic cells (DCs), both controlling the activation of CD4 þ Foxp3 À helper T cells. Utilizing mixed leukocyte reactions (MLRs) reflecting physiological interactions between T cells and DCs, we report that anti-CD4 treatment inhibits CD4 þ Foxp3 À T cell proliferation in an IL-2-independent fashion. Notably, YTS177.9 binding induces a rapid internalization of CD4 on both CD4 þ Foxp3 À T cells and Foxp3 þ Tregs. However, no expansion or activation of immunosuppressive CD4 þ Foxp3 þ Tregs was observed following anti-CD4 treatment. Additionally, cytokine production, maturation and T cell priming capacity of DCs are not affected by anti-CD4 exposure. In line with these data, the selective ablation of Foxp3 þ Tregs from MLRs by the use of diphtheria toxin (DT)-treated bacterial artificial chromosome (BAC)-transgenic DEREG mice completely fails to abrogate the suppressive activity of multiple anti-CD4 antibodies. Instead, tolerization is associated with the defective expression of various co-stimulatory receptors including OX40 and CD30, suggesting altered signaling through the TCR complex. Consistent with our findings in mice, anti-CD4 treatment renders human CD4 þ T cells tolerant in the absence of Tregs. Thus, our results establish that anti-CD4 antibodies can directly tolerize pathogenic CD4 þ Foxp3 À helper T cells. This has important implications for the treatment of human inflammatory diseases.
Allogeneic induced human FOXP3 + IFN-γ + T cells exhibit selective suppressive capacity
European Journal of Immunology, 2009
Human induced CD4 1 CD25 1 T cells have been shown to express FOXP3, similar to naturally occurring Treg cells (nTreg). However, the suppressive capacity of these cells is still under debate. The current study was designed to investigate functional characteristics of CD25 1 FOXP3 1 derived from CD25 À T cells. Stimulation of CD25 À PBMC with allogeneic PBMC resulted in production of CD4 1 CD25 high T cells. This process was more rapid and prominent when highly mature DC were used for stimulation. The resultant CD4 1 CD25 high population concurrently exhibited regulatory markers FOXP3, CTLA-4, GITR, and inflammatory cytokines IL-2 and IFN-c. These human-induced FOXP3 1 IFN-c 1 T cells were shown, for the first time, to markedly inhibit alloreactive T-cell expansion, similar to nTreg. However, in contrast to nTreg, the induced CD4 1 CD25 1 FOXP3 1 cells did not suppress proliferation against a third party donor stimulus or CMV. This suggested that the cell population possessed a more selective suppressive capacity targeted against the original stimulus only. The induced human CD4 1 CD25 1 FOXP3 1 subset derived from CD25 À T cells, while expressing inflammatory cytokines, exhibits a suppressive cell contact-dependent effect, restricted against T cells responding to the original stimulus. Such unique properties suggest that these cells are potentially ideal for the use as post-transplant GVH disease prophylaxis.