IL-2 Ameliorates Chronic GVHD by Inducing Antigen-Specific Regulatory T Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2654-2654
Author(s):  
Jens G. Lohr ◽  
Birgit Knoechel ◽  
Estelle C. Kahn ◽  
Abul K. Abbas
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cd4 T Cells ◽  
Chronic Gvhd ◽  
The Self ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Peripheral Tissues ◽  
Self Antigen

Abstract We have developed a mouse model in which a GvHD-like syndrome develops in response to a defined soluble self-antigen. This phenotype is caused after transfer of CD4+ T cells that have a single specificity and are reactive to the self-antigen into a lymphopenic host that expresses the cognate antigen. By using a clonotypic antibody we are able to identify these cells and can therefore follow their migration, kinetics and functional characteristics. At least two distinct phases can be identified by clinical picture and correlated with accumulation of T cells - an early phase, resembling acute GvHD, leading to wasting and death coinciding with rapid accumulation of T cells, and a late phase in which a stable number of T cells is maintained clinically reminiscent of chronic GvHD. We show here that a fraction of the naïve T cells that encounter the self-antigen after transfer develop into CD4+CD25+ regulatory T cells (Treg) in the periphery. This population controls T cell homeostasis, activation and severe immune pathology. The development of CD4+CD25+ Treg critically depends on IL-2 produced by the T cells. Therefore, in the absence of IL-2, T cell homeostasis cannot be maintained and massive accumulation of CD4+ T cells leads to severe inflammation of the skin. Importantly, only IL-2 that is produced by the T cells themselves, but not from peripheral tissues, leads to efficient generation of Treg and T cell homeostasis. We suggest that Treg-development is a differentiation step of T cells that encounter self-antigen in the periphery, and is essential for maintaining homeostasis even in the presence of self-recognition. Our data provide mechanistic insight into the re-establishment of homeostasis after cell transfer into a lymphopenic host and have important implications for the use and timing of therapeutic approaches targeting the IL-2 pathway.

scholarly journals TSLP and IL-7 use two different mechanisms to regulate human CD4+ T cell homeostasis

2009 ◽  
Vol 206 (10) ◽  
pp. 2111-2119 ◽  
Author(s):  
Ning Lu ◽  
Yi-Hong Wang ◽  
Yui-Hsi Wang ◽  
Kazuhiko Arima ◽  
Shino Hanabuchi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Th2 Cells ◽  
T Cell Proliferation ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Th2 Differentiation

Whether thymic stromal lymphopoietin (TSLP) directly induces potent human CD4+ T cell proliferation and Th2 differentiation is unknown. We report that resting and activated CD4+ T cells expressed high levels of IL-7 receptor a chain but very low levels of TSLP receptor (TSLPR) when compared with levels expressed in myeloid dendritic cells (mDCs). This was confirmed by immunohistology and flow cytometry analyses showing that only a subset of mDCs, with more activated phenotypes, expressed TSLPR in human tonsils in vivo. IL-7 induced strong STAT1, -3, and -5 activation and promoted the proliferation of naive CD4+ T cells in the presence of anti-CD3 and anti-CD28 monoclonal antibodies, whereas TSLP induced weak STAT5 activation, associated with marginally improved cell survival and proliferation, but failed to induce cell expansion and Th2 differentiation. The effect of TSLP on enhancing strong human T cell proliferation was observed only when sorted naive CD4+ T cells were cultured with mDCs at levels as low as 0.5%. TSLP could only induce naive CD4+ T cells to differentiate into Th2 cells in the presence of allogeneic mDCs. These results demonstrate that IL-7 and TSLP use different mechanisms to regulate human CD4+ T cell homeostasis.

The Elevated Ratio of Peripheral Blood CD27−CD4+ T Cells in Patients Received Allogeneic Stem Cell Transplantation Implies Altered T Cell Homeostasis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1413-1413
Author(s):  
Akiko Fukunaga ◽  
Takayuki Ishikawa ◽  
Takero Shindo ◽  
Sumiko Takao ◽  
Toshiyuki Hori ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cd4 T Cells ◽  
Immune Reconstitution ◽  
Cd4 T Cell ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Effector Cells

Abstract One of the major problems following allogeneic stem cell transplantation (allo-SCT) is the inability to reconstitute an adequate immune system for an extended period. T-cell reconstitution is also delayed for years, especially in CD4+ T cells. In addition to impaired thymic function, shortened Naive T cell survival due to altered T cell homeostasis is reported to be responsible for delayed immune reconstitution. To further investigate the mechanisms of delayed immune recovery after allo-SCT, we focused on the frequencies of effector CD4+ T cells, because according to the previous reports, progressive linear differentiation model of CD4+ T cell predicts the accumulation of terminally differentiated effector cells when transition from naïve to memory T cells and memory to effector cells are accelerated. By flowcytometric analyses we confirmed that CD27−CD4+ T cells from allo-SCT recipients uniformly express CD95, with negative expression of CCR7 and CD62L. They also produce g-interferon (IFNg) in response to the immobilized anti-CD3 and soluble anti-CD28 stimulation, which is consistent with previous reports insisting that CD27−CD4+ T cells are functionally differentiated effector T cells. Measuring the ratio of CD27−CD4+ T cells among CD4+ T cells revealed that, although healthy donors and patients received allo-SCT within a year had comparable CD27+CD4+T-cell rate (90% vs. 83%, P=0.4436), significantly decreased rate was observed in patients transplanted more than 1 year before (55% vs. 83%, P=0.0005). The ratio of CD27+CD4+ T cells kept low during the first 5 years after allo-SCT, and then it slowly begun to increase. In addition, in patients who received stem cell grafts more than 1 year before, the ratio of CD27+CD4+ T cells were significantly higher in patients transplanted from HLA-matched siblings than in those received unrelated grafts (69% vs. 42%, P=0.0002). Other factors, such as stem cell source (BM or PBSC), patient age, and the presence of chronic GVHD did not influence the ratio of CD27+CD4+ T cells. To further investigate the characteristics of CD27−CD4+ T cells in post-transplant periods, peripheral CD4+ T cells from patients who had received allo-SCT more than 1 year before as well as healthy volunteers were sorted into CD27− and CD27+ fractions, stained with CFSE, and stimulated with immobilized anti-CD3 and soluble anti-CD28 antibodies. CD27−CD4+ T cells proliferated more vigorously at 3 days after stimulation, though after another 2-day culture, there was no difference in cell divisions between both cell groups. In addition, CD27+ cells from transplanted patients lost their expression more frequently than those from volunteers, while none of the CD27− cells stored its expression. The fact of one-way transition from CD27+ to CD27− also supported that CD27−CD4+ T cells are terminally differentiated T cells. The finding that the frequencies of CD27−CD4+ T cells begin to elevate at 1 year after allo-SCT indicates that T cells infused with allograft do not easily lose the surface expression of CD27, while T cells derived from donor’s stem cells do. Considering the fact that ratio of CD27−CD4+ T cells is much higher in recipients of unrelated grafts, and it gradually begin to decrease at 5 years after allo-SCT, the increased ratio of CD27−CD4+ T cells may reflect altered T cell homeostasis. The serial monitoring of the ratio of CD27−CD4+ T cells after allo-SCT may be useful in evaluating immune reconstitution status.

Altered Naive and Memory T Cell Homeostasis and Immunosenescence Characterize Younger Patients with Immunosuppressive-Responsive Myelodysplastic Syndrome

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3647-3647
Author(s):  
JianXiang Zou ◽  
Dana E Rollison ◽  
David Boulware ◽  
Elaine M. Sloand ◽  
Loretta Pfannes ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immunosuppressive Therapy ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Effector Memory ◽  
Cell Populations ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Younger Patients

Abstract BACKGROUND: A subset of patients with Myelodysplastic Syndrome (MDS) responds well to immunosuppressive therapy (IST) and the only validated predictor of response is age, with younger patients faring much better than older patients. Hematologic improvement on immunosuppressive therapy is associated with a survival benefit with response rates ranging from 15% to 50%, clearly comparable or better than results with other existing therapies in MDS. Despite progress in the basic understanding of immune pathobiology of MDS and a clear therapeutic value, including improved long-term survival, IST including anti-thymocyte globulin (ATG) and/or cyclosporine A (CyA) is rarely offered to MDS patients in the U.S. due to uncertain criteria for selection of patients and potential toxicities. In addition, there is an underlying concern that inappropriate use of immunosuppressive therapy may negatively impact risk for leukemia progression, which occurs in 30–40% of MDS cases. The long-term goal of this study is to identify an immune signature that has postive predictive power for IST responsiveness. METHODS: To determine the effect of age on T-cell homeostasis and function and IST response, we performed a study of 54 MDS patients compared to 37 healthy controls. In a pilot study, T cell abnormalities associated with response to equine anti-lymphocyte globulin (eATG, lymphoglobulin, Pfizer, Inc) and/or CyA was studied in 12 younger MDS patients composed of 6 responders and 6 non-responders. RESULTS: CD4+ T-cells are normally present in the peripheral blood lymphocyte pool at 2 to 4 times greater than that of CD8+ T-cells, and diminished CD4:CD8 ratio has been previously shown to correlate with poor survival outcome in MDS. Similar to previous reports, we found that the age-adjusted CD4:CD8 ratio was reduced in MDS patients compared to healthy controls (p-value <0.0001) Interestingly, our analysis revealed that inadequate CD4+ rather than expansion of CD8+ T-cells was associated with a lower ratio in this group of MDS patients that included both lower and higher risk MDS patients defined by the International Prognostic Scoring System (IPSS). Analysis of the percentage of T-cells with naïve and memory phenoytpes using CD45RA and CD62L display, demonstrated positive correlations between age and both % CD62L positive naïve cells and central memory CD4+ T-cells (naïve: slope=0.39, p=0.12; central memory: slope=1.26, p=0.005). Furthermore, the proportions of CD62L- CD4+ T-cell populations, including effector memory and terminal effector memory T-cells, were greater in younger MDS patients (slope=−0.82, p=0.08 and slope=−0.83, p=0.015, respectively) suggesting a possible relationship to IST responsiveness. Specific characteristics associated with response to eATG in the pilot study of 12 younger patients included altered distribution of T cell populations (i.e., lower CD4/CD8 ratio, p<0.001) and higher constitutive proliferative index of the T cell populations (p=0.03 CD4+ and p=0.02 CD8+ T-cells, respectively). We also found that hematological response was associated with blockade of homeostatic proliferation of T cells associated with reconstitution of the naïve T cell pool. Reduction in CD4+ T-cells and expansion of autoreactive CD8+ T-cells suggests that apoptotic conditions may drive the expansion of cells through homeostatic cytokines such as IL-7, IL-15, and/or IL-21, which are all cytokines of the IL-2Rγc family that control homeostatic proliferation. Comparisons of the IL-7Ra, IL-15Ra, IL-2Ra, and IL-21Ra subunit demonstrated overexpression of IL-21Ra in patients 35.4% ± 3.4 in CD4+ T-cells and 31.8% ± 4.3 in CD8+ T-cells compared to healthy donors 0.9% ± 0.5 and 0.5% ± 0.5 (p<0.0001). CONCLUSIONS: Association between the T-cell abnormalities reported in this study and response to IST strongly suggests that aberrant T-cell homeostasis may represent a critical determinant of autoimmunity in MDS that may have positive predictive power for response to IST.

scholarly journals Bone marrow–based homeostatic proliferation of mature T cells in nonhuman primates: implications for AIDS pathogenesis

Blood ◽  
2009 ◽  
Vol 113 (3) ◽  
pp. 612-621 ◽  
Author(s):  
Mirko Paiardini ◽  
Barbara Cervasi ◽  
Jessica C. Engram ◽  
Shari N. Gordon ◽  
Nichole R. Klatt ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
T Cell Proliferation ◽  
Homeostatic Proliferation ◽  
T Cell Homeostasis ◽  
Cell Homeostasis

AbstractBone marrow (BM) is the key hematopoietic organ in mammals and is involved in the homeostatic proliferation of memory CD8+ T cells. Here we expanded on our previous observation that BM is a preferential site for T-cell proliferation in simian immunodeficiency virus (SIV)–infected sooty mangabeys (SMs) that do not progress to AIDS despite high viremia. We found high levels of mature T-cell proliferation, involving both naive and memory cells, in healthy SMs and rhesus macaques (RMs). In addition, we observed in both species that lineage-specific, BM-based T-cell proliferation follows antibody-mediated in vivo CD4+ or CD8+ T-cell depletion, thus indicating a role for the BM in maintaining T-cell homeostasis under depleting circumstances. We also observed that, in SIV-infected SMs, but not RMs, the level of proliferation of BM-based CD4+ T cells is higher than that of circulating CD4+ T cells. Interestingly, limited BM-based CD4+ T-cell proliferation was found in SIV-infected SMs with low CD4+ T-cell counts, suggesting a regenerative failure in these animals. Collectively, these results indicate that BM is involved in maintaining T-cell homeostasis in primates and suggest a role for BM-based CD4+ T-cell proliferation in determining the benign nature of natural SIV infection of SMs.

scholarly journals Burn injury induces a change in T cell homeostasis affecting preferentially CD4+T cells

2004 ◽  
Vol 77 (2) ◽  
pp. 141-150 ◽  
Author(s):  
Julie Patenaude ◽  
Michele D’Elia ◽  
Claudine Hamelin ◽  
Dominique Garrel ◽  
Jacques Bernier
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Burn Injury ◽  
T Cell Homeostasis ◽  
Cell Homeostasis

scholarly journals Regulatory T cells in the control of T cell homeostasis

2010 ◽  
Vol 30 (6) ◽  
pp. 502-506 ◽  
Author(s):  
Kimito Kawahata ◽  
Takeyuki Kanzaki ◽  
Mitsuru Imamura ◽  
Lisa Akahira ◽  
Kazuya Michishita ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Homeostasis ◽  
Cell Homeostasis

scholarly journals Age-associated increase in lifespan of naive CD4 T cells contributes to T-cell homeostasis but facilitates development of functional defects

2009 ◽  
Vol 106 (43) ◽  
pp. 18333-18338 ◽  
Author(s):  
H. Tsukamoto ◽  
K. Clise-Dwyer ◽  
G. E. Huston ◽  
D. K. Duso ◽  
A. L. Buck ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Functional Defects

scholarly journals Lineage-specific T-cell reconstitution following in vivo CD4+ and CD8+ lymphocyte depletion in nonhuman primates

Blood ◽  
2010 ◽  
Vol 116 (5) ◽  
pp. 748-758 ◽  
Author(s):  
Jessica C. Engram ◽  
Barbara Cervasi ◽  
Jose A. M. Borghans ◽  
Nichole R. Klatt ◽  
Shari N. Gordon ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Cell Repopulation

Abstract Many features of T-cell homeostasis in primates are still unclear, thus limiting our understanding of AIDS pathogenesis, in which T-cell homeostasis is lost. Here, we performed experiments of in vivo CD4+ or CD8+ lymphocyte depletion in 2 nonhuman primate species, rhesus macaques (RMs) and sooty mangabeys (SMs). Whereas RMs develop AIDS after infection with simian immunodeficiency virus (SIV), SIV-infected SMs are typically AIDS-resistant. We found that, in both species, most CD4+ or CD8+ T cells in blood and lymph nodes were depleted after treatment with their respective antibodies. These CD4+ and CD8+ lymphocyte depletions were followed by a largely lineage-specific CD4+ and CD8+ T-cell proliferation, involving mainly memory T cells, which correlated with interleukin-7 plasma levels. Interestingly, SMs showed a faster repopulation of naive CD4+ T cells than RMs. In addition, in both species CD8+ T-cell repopulation was faster than that of CD4+ T cells, with CD8+ T cells reconstituting a normal pool within 60 days and CD4+ T cells remaining below baseline levels up to day 180 after depletion. While this study revealed subtle differences in CD4+ T-cell repopulation in an AIDS-sensitive versus an AIDS-resistant species, such differences may have particular relevance in the presence of active SIV repli cation, where CD4+ T-cell destruction is chronic.

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