Th17/Th22 Cells Mediate Breakthrough Graft-Versus-Host-Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1878-1878
Author(s):  
Scott N. Furlan ◽  
Victor Tkachev ◽  
Ben Watkins ◽  
Kayla Betz ◽  
Angela Panoskaltsis-Mortari ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
T Cell Proliferation ◽  
Host Disease ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Flow Cytometric ◽  
Th1 Cytokine

Abstract Acute graft-versus-host disease (aGVHD) develops in more than half of patients after allogeneic hematopoietic cell transplantation (allo-HCT) despite poly-pharmacy immunoprophylaxis. Importantly, the dysregulated pathways responsible for this breakthrough disease remain largely unidentified. Thus, the discovery of these pathways represents one of the critical challenges for the field of allo-HCT. To address these needs, we have developed a model of aGVHD in rhesus macaques, which allows us to study the mechanisms of aGVHD both in its untreated state and in a variety of immunoprophylactic settings. Using a systems-based approach, we have created both a multiparameter flow cytometric and transcriptomic map of the immune landscape of aGVHD in allo-HCT recipients, in comparison to two critical control groups: (1) healthy untransplanted controls, and (2) those receiving autologous transplantation. We find that recipients of allo-HCT receiving 1) no immunoprophylaxis 2) monotherapy with CTLA4Ig or 3) monotherapy with sirolimus develop early fulminant aGVHD with multi-organ disease (Figure 1a-grouped as 'Primary GVHD'). The immunophenotype of T cells from the Primary GVHD cohort exhibits an effector/memory phenotype with robust proliferation and acquisition of cytotoxic function. Transcriptomic analysis reveals enrichment of Th1-associated transcripts (IL12RB2, CCR5, CXCR3) as well as programs of proliferation early in the post transplant period (Figure 1b). Flow cytometric data confirms an increase in the number of CD4 and CD8 T cells producing the Th1 cytokine, IFN-g at this time-point (Figure 1c). In contrast, standard-of-care Tacrolimus/Methotrexate (Tac/Mtx) as well as novel CTLA4Ig/sirolimus combination immunoprophylaxis (CoBS) both significantly improved survival of animals after allo-HCT. However, similar to human patients undergoing allo-HCT, these recipients often developed clinical signs of breakthrough aGVHD (starting around day 30 post-transplant) characterized by both gastrointestinal and skin pathology. This cohort was thus termed the "Breakthrough GVHD" cohort (Figure 1a). Unexpectedly, despite the presence of breakthrough clinical aGVHD, the Tac/Mtx and CoBS cohorts were still able to control programs of T cell proliferation, effector phenotype acquisition and Th1 cytokine skewing. However, both transcriptional and flow cytometric profiles demonstrated enrichment for molecules that reflect Th17/Th22 skewing (RORC, IL17A, AHR, and IL22) (Figure 2a) and production of IL17a (Figure 2b). These results suggest that while current methods of immunoprophylaxis are able to limit both T cell proliferation and Th1 polarization, breakthrough Th17/Th22 pathway activation occurs despite these therapies. These data suggest that emphasis should be placed on exploration of pharmacologic inhibitors of IL17/IL22 for the prevention/treatment of breakthrough aGVHD. Disclosures No relevant conflicts of interest to declare.

scholarly journals Indoleamine 2,3-dioxygenase is a critical regulator of acute graft-versus-host disease lethality

Blood ◽  
2008 ◽  
Vol 111 (6) ◽  
pp. 3257-3265 ◽  
Author(s):  
Lisa K. Jasperson ◽  
Christoph Bucher ◽  
Angela Panoskaltsis-Mortari ◽  
Patricia A. Taylor ◽  
Andrew L. Mellor ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Tissue Injury ◽  
T Cell Proliferation ◽  
Colonic Inflammation ◽  
Host Disease ◽  
Graft Versus Host ◽  
Indoleamine 2,3 Dioxygenase

AbstractGraft-versus-host disease (GVHD) is initiated after activation of donor T cells by host antigen-presenting cells (APCs). The immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) is expressed by APCs and parenchymal cells and is further inducible by inflammation. We investigated whether lethal conditioning and GVHD induce IDO and if IDO prevents tissue injury by suppressing immune responses at the induction site. We determined that IDO is a critical regulator of GVHD, most strikingly in the colon, where epithelial cells dramatically up-regulated IDO expression during GVHD. IDO−/− mice died more quickly from GVHD, displaying increased colonic inflammation and T-cell infiltration. GVHD protection was not mediated by control of T-cell proliferation, apoptosis, or effector mechanisms in lymphoid organs, nor did it require donor T regulatory cells. Instead, T cells in IDO−/− colons underwent increased proliferation and decreased apoptosis compared with their wild-type counterparts. This evidence suggests that IDO can act at the site of expression to decrease T-cell proliferation and survival, diminishing colonic inflammation and reducing disease severity. These studies are the first to identify a function for IDO in GVHD lethality and indicate that modulation of the IDO pathway may be an effective strategy for treatment of this disease.

Donor Requirements For CD4+CD25+FoxP3+ Regulatory T Cells Capable Of Suppressing CD4+ and CD8+ Conventional T Cell Proliferation and Graft Versus Host Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4484-4484 ◽  
Author(s):  
Antonio Pierini ◽  
Lucrezia Colonna ◽  
Maite Alvarez ◽  
Dominik Schneidawind ◽  
Byung-Su Kim ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Animal Models ◽  
Graft Versus Host Disease ◽  
Third Party ◽  
T Cell Proliferation ◽  
Graft Versus Host

Adoptive transfer of CD4+CD25+FoxP3+ regulatory T cells (Tregs) prevents graft versus host disease (GvHD) in several animal models and following allogeneic hematopoietic cell transplantation (HCT) in clinical trials. In these models donor derived Tregs have been mainly used as they share the same major histocompatibility complex (MHC) with conventional CD4+ and CD8+ T cells (Tcons) that are primarily responsible for GvHD onset and persistence. Third-party derived Tregs are a promising alternative tool for cellular therapy as they can be prepared in advance, screened for pathogens and activity and banked. In this study we explored MHC disparities between Tregs and Tcons in HCT to evaluate the impact of these different cell populations in GvHD prevention and survival after transplant. Methods and Results We evaluated the ability of highly purified Treg to suppress proliferation of C57BL/6 (H-2b) Tcons following exposure to irradiated splenocytes from BALB/C (H-2d) mice in vitro in a mixed lymphocyte reaction (MLR). Either donor derived C57BL/6 (H-2b) or third party FVB (H-2q) Tregs suppressed Tcon proliferation at the Treg/Tcon ratios of 1:2 and 1:4. The same Treg population effectively suppressed different MHC derived Tcons where BALB/C (H-2d) or FVB (H-2q, third-party) Tcons were incubated with irradiated splenocytes from C57BL/6 (H-2b) mice and were effectively suppressed with BALB/C (H-2d) Tregs. In the MLR, third-party Tregs present the same activation molecule expression patterns as MHC matched Tregs: CTLA4 and LAG3 expression is enhanced after stimulation with interleukin-2 (IL-2) and anti-CD3/CD28 beads, while MHC class II molecule expression is increased after 3-4 days of culture with Tcons and irradiated splenocytes. Furthermore third-party and MHC matched Tregs express the same levels of interleukin-10 (IL-10). We translated these results to in vivo studies in animal models. In these studies T cell depleted bone marrow (TCD BM) from C57BL/6 (H-2b) mice was injected into lethally irradiated (total body irradiation, 8 Gy) BALB/C (H-2d) recipient mice. 2 days later GvHD was induced by injecting luc+ donor derived Tcons (1x106/mouse). Using this model GvHD was evaluated following the adoptive transfer of freshly isolated CD4+CD25+FoxP3+ Tregs derived from BALB/C (H-2d, host type), C57BL/6 (H-2b, donor type), FVB (H-2q, third-party) or BALB/B (H-2b, minor mismatched with the donor, major mismatched with the host) mice at the different Treg/Tcon ratios of 1:1, 1:2 and 1:4. As expected, donor Tregs exerted the strongest dose dependent GvHD protection (p = 0.028), while host Tregs did not improve mouse survival (p = 0.58). Third-party and minor mismatched with the donor Tregs improved mouse survival (third-party and minor mismatched with the donor respectively, p = 0.028 and p = 0.17) but mice had worse GvHD score profiles (both p< 0.001) and could not recover their weight as well as mice treated with donor Tregs (both p< 0.001). In vivoTcon bioluminescent imaging confirmed these results showing a reduced Tcon proliferation in mice treated with donor, third-party and minor mismatched with the donor Tregs, the first exerting the strongest effect (after 6 weeks of observation, p< 0.001). Conclusions Our studies indicate that MHC disparities between Tregs and Tcons do not represent an insurmountable barrier for Treg function. In vitro and in vivo data strongly suggest that Tregs can suppress Tcon proliferation without requiring MHC matching. In vivo GvHD prevention efficiency was affected by MHC disparities with donor derived Treg being the most effective, however, third party Treg also resulted in GvHD attenuation. These studies indicate that both donor and third party Treg could be effective in clinical application raising the possibility of screening and banking Treg for use. Further, these studies highlight the need for activation of the Treg on host tissues to effectively suppress conventional T cell proliferation and GvHD induction. Disclosures: No relevant conflicts of interest to declare.

Discovery and Validation of STAT-3 and ERK1/2 Phosphorylation as Critical for the Function of Alloactivated T Cells in Acute Graft-Versus-Host-Disease Via a Novel Technique for Drug Discovery.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3236-3236
Author(s):  
Sydney X. Lu ◽  
Onder Alpdogan ◽  
Roberto Campos ◽  
Xiao Wang ◽  
Guo-Jian Gao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Drug Targets ◽  
Cytokine Signaling ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Flow Cytometric

Abstract Graft-versus-host-disease (GVHD) is a serious complication of allogeneic bone marrow transplantation (allo-BMT). The physiology of GVHD is dominated by alloactivated donor T cells, yet current treatments are often nonspecific and offer limited efficacy with relatively high toxicities. We screened for novel drug targets in alloactivated T cells in a murine allo-BMT model using a flow cytometric technique for the in vivo analysis of intracellular signaling. We defined the signaling profile of normal T cells and alloreactive T cells during GVHD, focusing on pathways involved in T cell receptor (TCR), costimulatory, and cytokine signaling. This analysis revealed that although proteins in multiple pathways (MAP kinases, PI3K, Jak/STAT signaling) were all heavily phosphorylated in alloactivated T cells, phosphorylation of STAT-3 and ERK1/2 were particularly prominently increased in donor alloactivated CD4 T cells. We further analyzed the importance of STAT-3 and ERK1/2 signaling in alloactivated T cells via the use of small-molecule inhibitors of STAT-3 (curcurbitacin E/I) and ERK1/2 phosphorylation (SL327). Treatment with these inhibitors attenuated T cell proliferation in response to anti-CD3+CD28 stimulation and in mixed leukocyte reactions in vitro in a dose-dependent fashion (figure 1). Figure 1 Figure 1. Pre-incubation of donor splenocytes with cucurbitacin E significanly reduced T cell activation (CD25, CD69) at 24 hours in adoptive transfer experiments in vivo (p<0.05). To rule out any direct toxicity, we analyzed recovered cells for apoptosis by Annexin-V staininga dn detected no significant toxicity (figure 2). Figure 2 Figure 2. We conclude that flow cytometric analysis of signaling pathways in single cells represents a novel methodology to assess the in vivo signaling profiles of specific cell populations in order to select drug targets for further study. STAT-3 and ERK1/2 phosphorylation may also represent potential targets to selectively inhibit donor T cell alloactivation and proliferation in GVHD.

Immunomodulatory Effects of Vitamin D: Implications for the Prevention and Treatment of Graft Versus Host Disease

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1251-1251
Author(s):  
Jacalyn Rosenblatt ◽  
Adam Bissonnette ◽  
Zekui Wu ◽  
Baldev Vasir ◽  
Corrine Zarwan ◽  
...  
Keyword(s):  
Vitamin D ◽  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Tritiated Thymidine ◽  
Antigen Presenting Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Antigen Presenting

Abstract Allogeneic bone marrow transplantation is a uniquely curative therapy for a subset of patients with hematologic malignancies. However, morbidity and mortality related to graft versus host disease remain substantial. Dendritic cells (DCs) are highly potent antigen presenting cells that play a crucial role in maintaining the balance of immune activation and tolerance as well as the nature of immune reconstitution post-transplant. Persistence of host DCs in the early post transplant period has been shown to play an important role in the activation and expansion of alloreactive lymphocytes and the concomitant risk of GVHD. A major focus of research to enhance outcomes following allogeneic transplantation involves the manipulation of DC recovery post-transplant to minimize activation of alloreactive lymphocytes while preserving anti-tumor immunity responsible for the graft versus disease effect. Vitamin D is a hormone involved in bone metabolism and calcium homeostasis. More recently, vitamin D has been shown to have potent immunomodulatory effects. We have evaluated the effect of vitamin D on the phenotypic and functional characteristics of DC and T cell populations. We have demonstrated that vitamin D hinders the maturation of DCs such that cells that are differentiated in its presence exhibit decreased expression of costimulatory molecules. Peripheral blood mononuclear cells (PBMCs) were isolated from leukopaks obtained from normal donors by ficoll density centrifugation. DCs were generated by culturing the monocyte enriched adherent fraction with GM-CSF (1000 U/ml) and IL-4 (1000 U/ml) for 5 days, followed by maturation in the presence of TNFa (25 ng/ml) for 48 hours. DCs were generated in the presence and absence of 10nM of 1,25 hydroxyvitamin D. Mean expression of the costimulatory molecule CD80 and the maturation marker CD83 decreased from 60% to 37% and 53% to 27% respectively in the presence of vitamin D (N=3). To assess the effect of vitamin D on the functional potency of DCs as antigen presenting cells, the capacity of mature DCs to stimulate allogeneic T cell proliferation in the presence of vitamin D was determined. Mature DCs were generated from peripheral blood precursors and then cultured with allogeneic T cells isolated by T cell separation column at a ratio of 1:10. After 5 days, cocultures were pulsed with tritiated thymidine overnight and proliferation was determined by measuring the stimulation index (SI) as defined by uptake of tritiated thymidine of cocultured cells/uptake of tritiated thymidine of T cells alone. Results of 10 serial studies demonstrated the addition of vitamin D resulted in a blunted T cell proliferative response, with mean SI that decreased from 13 to 5. Similarly, the addition of vitamin D to a coculture of DCs and autologous T cells resulted in a 50% reduction in the T cell proliferative response to tetanus toxoid, a recall antigen. In addition, T cells stimulated by allogeneic DCs in the presence of vitamin D were polarized to secrete Th2 cytokines. In three experiments, the mean percentage of T cells secreting IL-10 increased from 2.7% to 4.4%, while expression of IFNγ decreased from a mean of 2.6% to 1.9% in the presence of vitamin D. The presence of vitamin D did not induce FOXP3 expressing regulatory T cell populations, which accounted for 8% and 7% of the T cell population following stimulation by allogeneic DCs in the presence and absence of vitamin D respectively. These data suggest that exposure to vitamin D exerts a tolerizing influence on T cells mediated by its impact on antigen presenting cells. Vitamin D may therefore have a role in the prevention and treatment of graft versus host disease. A clinical trial evaluating the use of vitamin D in the early post-transplant period for the prevention of GVHD is planned.

Host Tissue PD-1 Pathway Contribute To Murine Chronic Graft-Versus-Host Disease Via Th1+Th17+ Cells

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3244-3244
Author(s):  
Hideaki Fujiwara ◽  
Yoshinobu Maeda ◽  
Koichiro Kobayashi ◽  
Hisakazu Nishimori ◽  
Ken-ichi Matsuoka ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Graft Versus Host Disease ◽  
Early Phase ◽  
Hematopoietic Cells ◽  
Chimeric Mice ◽  
Host Disease ◽  
Graft Versus Host ◽  
Post Transplant

Abstract Chronic graft-versus-host disease (cGVHD) remains a major cause of late-phase mortality and morbidity after allogeneic hematopoietic stem cell transplantation. Programmed death-1 (PD-1) and its ligands B7H1 and B7DC, which deliver inhibitory signals and regulate T cell activation, tolerance, and immunopathology, are involved in autoimmune disease. Although several studies have shown that blocking the PD-1 pathway enhances acute GVHD, its relationship to cGVHD remains unclear. We investigated the role of the PD-1 pathway in cGVHD, using a well-defined mouse cGVHD model. Recipients received 6 Gy TBI and were transplanted with purified splenic T cells and BM from either syngeneic BALB/c or allogeneic B10.D2 donors. On days 14, 21, 28, and 56 post-transplant, CD4 and CD8 cells from the spleens and peripheral lymph nodes (pLN) in the allogeneic recipients expressed significantly more PD-1 than those in the syngeneic recipients (p<0.005). Allogeneic recipients had elevated B7H1 mRNA levels from day 14-28 post-transplant (p<0.05) and immunohistochemical analysis of skins from allogeneic recipients showed more B7-H1 expression than from syngeneic recipients on days 14-28 post-transplant, while this declined to the same level as in the syngeneic group after day 42. These findings suggest that donor cells express more PD-1, while target tissues of recipients transiently up-regulate B7H1 expression only in the early phase and soon down-regulate it to syngeneic levels. Upon transfer of PD-1-/- donor T cells with the B10.D2 background into allogeneic BMT models, weight loss was severe and 100% of the recipients died by day 23 post-transplant. To avoid early death, we administered antibodies blocking the PD-1 pathway to recipients of WT donors beginning on day 14 post-transplant, just before they developed clinical signs of cGVHD. Mice treated with anti-PD-1 Ab showed 70% mortality by day 35 and 10% mortality was seen in those given anti-B7H1 Ab or anti-B7DC Ab. All groups treated with anti-PD-1, anti-B7H1, or anti-B7DC Ab had significantly higher cGVHD scores than controls (p<0.05). We next used B7H1-/- mice with the BALB/c background as recipients to evaluate how host B7H1 expression contributes to cGVHD. Allogeneic B7H1-/- recipients showed significantly more severe skin cGVHD and histopathological damage than WT controls (5.86 ± 0.85 vs. 8.38 ± 0.38, p<0.05). We previously elucidated the contribution of Th1+Th17+T cells to cGVHD and Am80, a potent synthetic retinoid, regulated both Th1 and Th17 responses, resulting in an attenuation of cGVHD (Nishimori et al. Blood 2012). Recipients of B7H1-/- showed fewer Foxp3+ regulatory T cells in the early phase (day 14, 13.5±4.2% vs. 6.4±4.4%, p<0.05), whereas there was no difference in the frequency of Foxp3+ regulatory T cells in the late transplantation period (day 28), as compared to WT recipients. Th1+Th17+T cells were detected significantly more frequently in recipients of B7H1-/- donors than those of WT recipients (day 28 2.7±0.35% vs. 1.4±0.2%, p<0.05). Administration of Am80 reduced Th1+Th17+T cells and cGVHD damage in recipients of B7H1-/- donors. To explore the contribution of B7H1 expression on hematopoietic cells or non-hematopoietic cells to cGVHD, (B7H1-/-→WT), (WT→B7H1-/-), and (WT→WT) chimeric mice (BALB/c background) were created by reconstituting sublethally irradiated WT or B7H1-/- Balb/c mice with BM cells from WT or B7H1-/- BALB/c mice. There were no differences in the clinical and pathological cGVHD scores between (B7H1-/-→WT) and (WT→WT) chimeric mice. CD4+CD25+ Foxp3+ Treg cells from (B7H1-/-→WT) recipients were detected less frequently on day 14 than in (WT→WT) recipients (p<0.05), but at similar levels on days 21 and 28. These findings suggest that B7H1 expression on hematopoietic cells plays a role in the development of Tregs only during the early transplantation period, but does not affect cGVHD severity. Unlike (B7H1-/-→WT) recipients, (WT→B7H1-/-) chimeras had significantly worse clinical cGVHD scores (p<0.05), histopathological damage (p<0.05), and Th1+Th17+T cell expansion (p<0.05), but no Treg cell changes. Collectively, these findings indicated that B7H1 expression on host tissues was dedicated to the expansion of IFN-g/IL-17 double-positive cells leading to cGVHD and that modulation of the tissue expression of B7-H1 might represent a new strategy for preventing or treating cGVHD. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Blockade of CD28 by a synthetical peptoid inhibits T-cell proliferation and attenuates graft-versus-host disease

2010 ◽  
Vol 7 (2) ◽  
pp. 133-142 ◽  
Author(s):  
Na Li ◽  
Faliang Zhu ◽  
Fei Gao ◽  
Qun Wang ◽  
Xiaoyan Wang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
T Cell Proliferation ◽  
Host Disease ◽  
Graft Versus Host

Post‐transplant cyclophosphamide limits reactive donor T cells and delays the development of graft‐versus‐host disease in a humanised mouse model

Immunology ◽  
2021 ◽  
Author(s):  
Sam Raj Adhikary ◽  
Peter Cuthbertson ◽  
Leigh Nicholson ◽  
Katrina M. Bird ◽  
Chloe Sligar ◽  
...  
Keyword(s):  
T Cells ◽  
Mouse Model ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Donor T Cells

scholarly journals Aberrant regulation of superantigen responses during T-cell reconstitution and graft-versus-host disease in immunodeficient mice

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2216-2224
Author(s):  
David Spaner ◽  
Xiaofang Sheng-Tanner ◽  
Andre C. Schuh
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Adoptive Transfer ◽  
Scid Mice ◽  
Control Mechanisms ◽  
Activated T Cells ◽  
Host Disease ◽  
Immunodeficient Mice ◽  
Graft Versus Host

Acute graft-versus-host disease (GVHD) after allogeneic stem cell transplantation is associated with impaired deletion and anergy of host-reactive T cells. To elucidate the immunoregulatory events that may contribute to such dysregulated T-cell responses in GVHD, we studied superantigen (SAg) responses after adoptive T-cell transfer into severe combined immunodeficient (SCID) mice. SAg responses are normally regulated by mechanisms involving deletion and anergy, with SAg-reactive T cells typically being deleted rapidly in vivo. In a SCID mouse model of GVHD, however, allogeneic host SAg-reactive T cells were not deleted rapidly, but rather persisted in increased numbers for several months. Moreover, depending on the timing of SAg stimulation and the numbers of T cells transferred, dysregulation (impaired deletion and anergy) of SAg responses could be demonstrated following the adoptive transfer of syngeneic T cells into SCID mice as well. Transgenic T-cell receptor-bearing KJ1-26.1+ T cells were then used to determine the fate of weakly reactive T cells after adoptive transfer and SAg stimulation. When transferred alone, KJ1-26.1+ T cells demonstrated impaired deletion and anergy. In the presence of more strongly staphylococcal enterotoxin B (SEB)–reactive T cells, however, KJ1-26.1+ T cells were regulated normally, in a manner that could be prevented by inhibiting the effects of more strongly SEB-reactive cells or by increasing the level of activation of the KJ1-26.1+ T cells themselves. We suggest that the control mechanisms that normally regulate strongly activated T cells in immunocompetent animals are lost following adoptive transfer into immunodeficient hosts, and that this impairment contributes to the development of GVHD.

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