scholarly journals The mouse gut T lymphocyte, a novel type of T cell. Nature, origin, and traffic in mice in normal and graft-versus-host conditions.

1978 ◽  
Vol 148 (6) ◽  
pp. 1661-1677 ◽  
Author(s):  
D Guy-Grand ◽  
C Griscelli ◽  
P Vassalli
Keyword(s):  
T Cells ◽  
Mast Cells ◽  
T Lymphocytes ◽  
Intestinal Mucosa ◽  
Cell Types ◽  
Intraepithelial Lymphocytes ◽  
Graft Versus Host ◽  
Dividing Cells ◽  
Gut Mucosa ◽  
Chediak Higashi Syndrome

Lymphocytes of the mouse intestinal mucosa, identified in tissue sections or purified suspensions of intraepithelial lymphocytes as T cells (gut T lymphocytes [GTL]), were studied in normal mice or in beige mice (the equivalent of the Chediak-Higashi syndrome in man, characterized by giant granules in various cell types, including mast cells). Mice were studied in normal or in germ-free conditions, or during a graft versus host (GVH) reaction resulting from the injection of parental thymocytes into lethally irradiated F1 mice, a condition leading to massive accumulation of T lymphocytes of donor origin in the host gut mucosa. In normal as well as in GVH conditions, a high percentage of the gut IE lymphocytes contain granules (up to 80% in the beige mouse). These granules have ultrastructural, hostochemical and other features resembling those of mast cell granules; in beige mice, up to 50% of them can be shown to contain histamine. Granulated T cells are also found in the lamina propria. It appears that the GTL may progressively lose their surface T antigens when the granules become more developed. Kinetics of [3H]TdR labeling of the GTL, transfer experiments with T cells of various origins, selective [3H]TdR labeling and selective irradiation of the Peyer's patches (PP), and effect of thoraic duct (TD) drainage led to the conclusion that GTL are the progeny of T cells stimulated to divide in the PP microenvironment, which endows them with a gut-homing tendency. From the PP, these cells follow a cycle, migrating to the TD and to the blood to colonize the whole intestinal mucosa, the majority of them as dividing cells undergoing a single round of traffic, with some probably able to recirculate and becoming a more long-lived variety. Antigenic stimulation within the PP is necessary for the emergence of GTL progenitors, but their gut-homing property is unrelated to the antigen as shown with fetal gut grafts, notably in GVH where grafts syngeneic to the host or donor become similarly infiltrated by GTL. On the basis of their properties and of further evidence to be reported elsewhere, it is proposed that GTL belong to a special class of T lymphocytes, related to the immune defenses of the mucosal systems in general, and capable of acting as progenitors of mucosal mast cells.

scholarly journals Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth.

1986 ◽  
Vol 163 (5) ◽  
pp. 1037-1050 ◽  
Author(s):  
J H Kehrl ◽  
L M Wakefield ◽  
A B Roberts ◽  
S Jakowlew ◽  
M Alvarez-Mon ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Transforming Growth Factor Beta ◽  
Potential Role ◽  
Transforming Growth Factor ◽  
Cell Types ◽  
Tgf Beta ◽  
Activated T Cells ◽  
Growth Factor Beta

This study examines the potential role of transforming growth factor beta (TGF-beta) in the regulation of human T lymphocyte proliferation, and proposes that TGF-beta is an important autoregulatory lymphokine that limits T lymphocyte clonal expansion, and that TGF-beta production by T lymphocytes is important in T cell interactions with other cell types. TGF-beta was shown to inhibit IL-2-dependent T cell proliferation. The addition of picograms amounts of TGF-beta to cultures of IL-2-stimulated human T lymphocytes suppressed DNA synthesis by 60-80%. A potential mechanism of this inhibition was found. TGF-beta inhibited IL-2-induced upregulation of the IL-2 and transferrin receptors. Specific high-affinity receptors for TGF-beta were found both on resting and activated T cells. Cellular activation was shown to result in a five- to sixfold increase in the number of TGF-beta receptors on a per cell basis, without a change in the affinity of the receptor. Finally, the observations that activated T cells produce TGF-beta mRNA and that TGF-beta biologic activity is present in supernatants conditioned by activated T cells is strong evidence that T cells themselves are a source of TGF-beta. Resting T cells were found to have low to undetectable levels of TGF-beta mRNA, while PHA activation resulted in a rapid increase in TGF-beta mRNA levels (within 2 h). Both T4 and T8 lymphocytes were found to make mRNA for TGF-beta upon activation. Using both a soft agar assay and a competitive binding assay, TGF-beta biologic activity was found in supernatants conditioned by T cells; T cell activation resulted in a 10-50-fold increase in TGF-beta production. Thus, TGF-beta may be an important antigen-nonspecific regulator of human T cell proliferation, and important in T cell interaction with other cell types whose cellular functions are modulated by TGF-beta.

scholarly journals Integrin crosstalk allows CD4+ T lymphocytes to continue migrating in the upstream direction after flow

2019 ◽  
Vol 11 (10) ◽  
pp. 384-393 ◽  
Author(s):  
Sarah Hyun Ji Kim ◽  
Daniel A Hammer
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Adhesion Molecule ◽  
Cell Types ◽  
Cellular Adhesion ◽  
Upstream Migration ◽  
Lymphocyte Function ◽  
Immune Functions ◽  
Cellular Adhesion Molecules ◽  
Upstream Direction

Abstract In order to perform critical immune functions at sites of inflammation, circulatory T lymphocytes must be able to arrest, adhere, migrate and transmigrate on the endothelial surface. This progression of steps is coordinated by cellular adhesion molecules (CAMs), chemokines, and selectins presented on the endothelium. Two important interactions are between Lymphocyte Function-associated Antigen-1 (LFA-1) and Intracellular Adhesion Molecule-1 (ICAM-1) and also between Very Late Antigen-4 (VLA-4) and Vascular Cell Adhesion Molecule-1 (VCAM-1). Recent studies have shown that T lymphocytes and other cell types can migrate upstream (against the direction) of flow through the binding of LFA-1 to ICAM-1. Since upstream migration of T cells depends on a specific adhesive pathway, we hypothesized that mechanotransduction is critical to migration, and that signals might allow T-cells to remember their direction of migration after the flow is terminated. Cells on ICAM-1 surfaces migrate against the shear flow, but the upstream migration reverts to random migration after the flow is stopped. Cells on VCAM-1 migrate with the direction of flow. However, on surfaces that combine ICAM-1 and VCAM-1, cells crawl upstream at a shear rate of 800 s−1 and continue migrating in the upstream direction for at least 30 minutes after the flow is terminated—we call this ‘migrational memory’. Post-flow upstream migration on VCAM-1/ICAM-1 surfaces is reversed upon the inhibition of PI3K, but conserved with cdc42 and Arp2/3 inhibitors. Using an antibody against VLA-4, we can block migrational memory on VCAM-1/ICAM-1 surfaces. Using a soluble ligand for VLA-4 (sVCAM-1), we can promote migrational memory on ICAM-1 surfaces. These results indicate that, while upstream migration under flow requires LFA-1 binding to immobilized ICAM-1, signaling from VLA-4 and PI3K activity is required for the migrational memory of CD4+ T cells. These results indicate that crosstalk between integrins potentiates the signal of upstream migration.

scholarly journals Specificity of Effector T Lymphocytes in Autologous Graft-Versus-Host Disease: Role of the Major Histocompatibility Complex Class II Invariant Chain Peptide

Blood ◽  
1997 ◽  
Vol 89 (6) ◽  
pp. 2203-2209 ◽  
Author(s):  
Allan D. Hess ◽  
Emilie C. Bright ◽  
Christopher Thoburn ◽  
Georgia B. Vogelsang ◽  
Richard J. Jones ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Lymphocytes ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Effector T Cells ◽  
Invariant Chain ◽  
Target Cells ◽  
Graft Versus Host ◽  
Histocompatibility Complex

Abstract Administration of the immunosuppressive drug cyclosporine after autologous bone marrow transplantation induces a systemic autoimmune syndrome resembling graft-versus-host disease (GVHD). This syndrome termed autologous GVHD has significant antitumor activity. Associated with autologous GVHD is the development of T lymphocytes that recognize major histocompatibility complex (MHC) class II determinants, including self. The present studies attempted to characterize and define the molecular specificity of the effector T lymphocytes in autologous GVHD induced in patients with metastatic breast cancer. The results suggest that the effector cells associated with human autologous GVHD are CD8+ T lymphocytes expressing the α/β T-cell receptor. Additional studies show that the effector T cells recognize MHC class II antigens in association with a peptide from the invariant chain (CLIP). Pretreatment of autologous lymphoblast target cells with anti-CLIP antibody completely blocked lysis mediated by autologous GVHD effector T cells. On the other hand, force loading this peptide markedly enhanced the susceptibility of the target cells to recognition by the autoreactive T cells. The recognition of the MHC class II CLIP complex may account for the novel specificity of the effector T cells associated with human autologous GVHD. Moreover, identification of the target peptide may allow for the development of novel immunotherapeutic strategies to enhance the antitumor efficacy of autologous GVHD.

P-glycoprotein targeting: a unique strategy to selectively eliminate immunoreactive T cells

Blood ◽  
2002 ◽  
Vol 100 (2) ◽  
pp. 375-382 ◽  
Author(s):  
Martin Guimond ◽  
Antonia Balassy ◽  
Mélanie Barrette ◽  
Sylvie Brochu ◽  
Claude Perreault ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Third Party ◽  
Cell Populations ◽  
Activated T Cells ◽  
Graft Versus Host ◽  
Histocompatibility Complex ◽  
P Glycoprotein ◽  
Selective Elimination

Abstract T lymphocytes have been found to harbor P-glycoprotein (Pgp) and to demonstrate modulation of its ion channel transporter function according to the state of activation of T lymphocytes. We hypothesized that cytotoxic chemicals that are extruded by Pgp could be used to specifically eliminate immunoreactive T-cell populations. In this study, we evaluated the capacity of 4,5-dibromorhodamine methyl ester (TH9402), a photosensitizer structurally similar to rhodamine, a dye transported by Pgp, and which becomes highly cytotoxic on activation with visible light to selectively deplete alloreactive T lymphocytes. Stimulation of T cells with mitogens or allogeneic major histocompatibility complex–mismatched cells resulted in the preferential retention of the TH9402 rhodamine-derivative in activated T cells, both CD4+ and CD8+. Photodynamic cell therapy of TH9402-exposed T cells led to the selective elimination of immunoreactive T-cell populations. In addition, this treatment preserved resting T cells and their capacity to respond to third-party cells. Inhibition of Pgp enhanced cellular trapping of the dye in nonactivated T cells and resulted in their depletion after exposure to light. Targeting of Pgp-deficient cells may therefore represent an appealing strategy for the prevention and treatment of graft-versus-host disease and other alloimmune or autoimmune disorders.

scholarly journals Quantitation of Colonic Cells as Severity Markers in Patients with Irritable Bowel Syndrome

2018 ◽  
Vol 7 ◽  
pp. e1063
Author(s):  
Mohammad Bagher Miri ◽  
Amir Sadeghi ◽  
Afshin Moradi ◽  
Mohammad Rostami-Nejad ◽  
Mohammad-Javad Ehsani-Ardekani ◽  
...  
Keyword(s):  
T Cells ◽  
Irritable Bowel Syndrome ◽  
Mast Cells ◽  
Inflammatory Cells ◽  
Normal Subjects ◽  
Intraepithelial Lymphocytes ◽  
Control Group ◽  
Case Group ◽  
Cross Sectional ◽  
Irritable Bowel

Background: Irritable bowel syndrome (IBS) is the most common gastrointestinal syndrome. Routine histopathology and immunohistochemistry (IHC) evaluations have shown an increase in the number of different inflammatory cells in the colon of IBS patients. In this study, we have compared the number of intraepithelial lymphocytes (IELs), eosinophils, mast cells and CD3+ T cells, in IBS patients and normal subjects. Materials and Methods: In 2016, seventy-nine patients with IBS and seventy-nine healthy subjects who underwent colonoscopy for other non-specific causes and with no pathologic findings, were enrolled in this cross-sectional study. Biopsy specimens obtained from the colon were stained, using IHC methods to determine the number of IELs, eosinophils, mast cells and CD3+ T cells. Quantitative and qualitative variables were compared between the two groups, using a Chi-square test and Student’s t-test. Results: Seventy-nine patients with IBS, 79.7% females with a mean age of 42.5±14.6 years, were recruited, as the case group, and seventy-nine individuals, 51.9% females with a mean age of 39.7±18.9 years, were enrolled as controls. The average number of IELs per high power fields (hpf) was found to be higher in the IBS group, and this difference was statistically significant (32.8±11.8 vs. 28.6±12.9; P=0.034). Also, the mean count/hpf of CD3+ T lymphocytes (23.1±7.9 vs. 20.2±8.1; P=0.024) and mast cells (7.6±3.1 vs. 6.6±3.0; P=0.041) were significantly higher in the IBS group, compared to the control group. The number of eosinophils was higher in the IBS group, but the differences were not statistically significant (P=0.066). Conclusion: According to the results, we suggest that analysis of immune cells and IELs in intestinal biopsies might be an appropriate method for diagnosis of IBS. [GMJ.2018;7:e1063]

scholarly journals Single-Cell Sequencing of Mouse Heart Immune Infiltrate in Pressure Overload–Driven Heart Failure Reveals Extent of Immune Activation

Circulation ◽  
2019 ◽  
Vol 140 (25) ◽  
pp. 2089-2107 ◽  
Author(s):  
Elisa Martini ◽  
Paolo Kunderfranco ◽  
Clelia Peano ◽  
Pierluigi Carullo ◽  
Marco Cremonesi ◽  
...  
Keyword(s):  
Heart Failure ◽  
T Cells ◽  
Mast Cells ◽  
Natural Killer Cells ◽  
Regulatory T Cells ◽  
Natural Killer ◽  
Immune Activation ◽  
Immune Cell ◽  
Pressure Overload ◽  
Cell Types

Background: Inflammation is a key component of cardiac disease, with macrophages and T lymphocytes mediating essential roles in the progression to heart failure. Nonetheless, little insight exists on other immune subsets involved in the cardiotoxic response. Methods: Here, we used single-cell RNA sequencing to map the cardiac immune composition in the standard murine nonischemic, pressure-overload heart failure model. By focusing our analysis on CD45 + cells, we obtained a higher resolution identification of the immune cell subsets in the heart, at early and late stages of disease and in controls. We then integrated our findings using multiparameter flow cytometry, immunohistochemistry, and tissue clarification immunofluorescence in mouse and human. Results: We found that most major immune cell subpopulations, including macrophages, B cells, T cells and regulatory T cells, dendritic cells, Natural Killer cells, neutrophils, and mast cells are present in both healthy and diseased hearts. Most cell subsets are found within the myocardium, whereas mast cells are found also in the epicardium. Upon induction of pressure overload, immune activation occurs across the entire range of immune cell types. Activation led to upregulation of key subset-specific molecules, such as oncostatin M in proinflammatory macrophages and PD-1 in regulatory T cells, that may help explain clinical findings such as the refractivity of patients with heart failure to anti–tumor necrosis factor therapy and cardiac toxicity during anti–PD-1 cancer immunotherapy, respectively. Conclusions: Despite the absence of infectious agents or an autoimmune trigger, induction of disease leads to immune activation that involves far more cell types than previously thought, including neutrophils, B cells, Natural Killer cells, and mast cells. This opens up the field of cardioimmunology to further investigation by using toolkits that have already been developed to study the aforementioned immune subsets. The subset-specific molecules that mediate their activation may thus become useful targets for the diagnostics or therapy of heart failure.

Modulation of Graft-Versus-Host Disease Induced by Central Memory Suicide Gene Modified Human T Lymphocytes.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1749-1749
Author(s):  
Bondanza Attilio ◽  
Valtolina Veronica ◽  
Magnani Zulma ◽  
La Seta Catamancio Simona ◽  
Benati Claudia ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Graft Versus Host Disease ◽  
Memory T Cells ◽  
Suicide Gene ◽  
Central Memory ◽  
Graft Versus Host ◽  
Ifn Γ ◽  
Functional Phenotype

Abstract Background. Suicide gene therapy is a promising approach for the safe exploitation of the graft-versus-leukemia effect. The insertion of Herpes Simplex Virus thymidine kinase confers an inducible suicidal phenotype upon ganciclovir (GCV) administration, thus enabling the selective elimination of T lymphocytes causing graft-versus-host disease (GvHD). Despite clinical and experimental studies substantiating the efficacy of the strategy, protocols to generate genetically modified cells (GMC) has been shown to reduce alloreactivity. The physiological CD4/CD8 ratio is inverted and GMC are enriched for “effector memory” T cells. Co-stimulation through CD28 has been shown to preserve the functional phenotype GMC. XcyteTM Dynabeads®, 4,5 μm anti-CD3 and anti-CD28 coated paramagnetic beads (bCD3/CD28) sustain T cell proliferation and can be used to obtain GMC. Aim. To in vitro characterize human suicide GMC generated with bCD3/CD28 GMC (XcyteTM Dynabeads®, Xcyte Therapies, Inc.) and to test their ability to engraft and cause GvHD in a xenogeneic mouse model. Results. bCD3/CD28 (bead to T cell ratio 3:1) are a potent stimulus for cell cycle entry for both CD4+ and CD8+ human T cells. This permits retroviral transduction (SFCMM#3 vector, Molmed SpA) and preservation of CD4/CD8 ratio. GMC generated with bCD3/CD28 are enriched for “central memory” T cells (CD45RA+CCR7+ 34±7%, CD28+CD27+ 67±12%, intracytoplasmic IL-2+ 14±5%, IFN-γ+ 10±3% and perforin+ 7±3%) when compared with GMC generated with anti-CD3 (CD3) alone (CD45RA+CCR7+ 17±4%, CD28+CD27+ 21±5%, intracytoplasmic IL-2+ 5±3%, IFN-γ+ 52±11% and perforin+ 22±4%). bCD3/CD28 GMC resist activation induced cell death (AxV+PI+ 12±3% vs 42±13% for CD3 GMC). When injected i.p. in NOD/SCID mice conditioned with irradiation and anti-NK depleting antibodies bCD3/CD28 GMC engraft with a faster kinetics (human chimerism at 2 weeks 14±7%) than observed for for CD3 GMC (5±2%). In this model, mice injected with unmodified human lymphocytes develop signs of xenogeneic (X-) GvHD (ruffled fur, hunched back, weight loss and finally death with massive accumulation of human T cell in lymphoid organs) by week 5. X-GvHD observed in mice injected with CD3 GMC has a significant slower course with a proportion of mice surviving week 8. X-GvHD caused by bCD3/CD28 GMC kill all the animals by week 7 (p<0,05 vs CD3 GMC). In mice with established X-GvHD caused by GMC treatment with GCV leads to a reduction in circulating GMC and modulates X-GvHD. GCV administration is not able to cure animals suffering from X-GvHD caused by unmodified T lymphocytes. Conclusions. GMC generated with bCD3/CD28 display a “central memory” functional phenotype and are significantly more efficient than CD3 GMC in causing lethal X-GvHD. GCV administration is able to abrogate X-GvHD caused by GMC. These results validate a tool for the generation of human suicide GMC with high alloreactive potential to be utilized in clinical protocols of adoptive immunotherapy of tumors.

Anti-Chronic Graft Versus Host Disease Activity Though a Regulatory T Cell Dependent Mechanism after Photodynamic Therapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3280-3280
Author(s):  
Jean-Philippe Bastien ◽  
Gorazd Krosl ◽  
Pascale Dube ◽  
Cynthia Therien ◽  
Christian Scotto ◽  
...  
Keyword(s):  
T Cells ◽  
Photodynamic Therapy ◽  
T Lymphocytes ◽  
Graft Versus Host Disease ◽  
Chronic Gvhd ◽  
Inhibitory Effect ◽  
Activated T Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
The Impact

Abstract Graft-versus-host disease (GVHD) is the principal cause of morbidity and mortality after hematopoietic stem cell transplantation. Even the most potent immunosuppressive agents often fail to control GVHD. Because of its unique cell-mediated approach, photopheresis represents an appealing alternative for the treatment of GVHD, particularly in its chronic form. Photodynamic therapy (PDT) using TH9402 (4,5-dibromorhodamine methyl ester), a photosensitizer, which upon activation with visible light, exhibits specific toxicity against activated T lymphocytes, while preserving resting T cells, has emerged as a potentially interesting alternative treatment modality for GVHD patients. However, the immunologic mechanisms involved in GVHD modulation by PDT still remain obscure. Since CD4+CD25+FoxP3+ regulatory T cells (Tregs) have an inhibitory effect on GVHD, we sought to determine the role of Tregs in the context of photopheresis using TH9402 for GVHD modulation. We first evaluated, using flow cytometry, the impact of PDT on activated T cells and Tregs obtained from steroid-refractory chronic GVHD patients. High (10 uM) and low (1,32 uM) TH9402 concentrations were compared to measure their ability preserve Tregs. Interestingly, low intensity TH9402 treatment demontrated particularly interesting features, resulting in the elimination of more than 90% of activated CD4+CD25+FoxP3- and CD4+CD44high T cells, while preserving 95% of CD4+CD25+ FoxP3+ cells (p<0.001; n=5 pts). The proportion of live CD4+CD25+ FoxP3+ cells increased from 51.8±5.2% to 89.0±5.9% (mean±SD; pre and post PDT, respectively; p<0.01) thus enriching the graft in Tregs. Next, we evaluated the ability of PDT treated mononuclear cells to inhibit the proliferation of untreated MNCs from cGVHD pts. The addition of PDT cells reduced the proliferation of cGVHD T lymphocytes by 41–76% (p<0.001, n=6 pts). This inhibitory effect disappeared following inhibition of Pgp-171 by verapamil, which promoted TH9402 intracellular retention and effector cell elimination upon light exposure, indicating that Tregs must not only be present but viable to exert their suppressive activity. In addition, higher levels of IL-10, but not TGF-β, were secreted when cGVHD cells were exposed to PDT-treated cells (34.7±5.1ng/mL) than when exposed to untreated cells (20.3±3.2ng/mL, p<0.05). Furthermore, the inhibitory effect decreased 5-fold when cGVHD cells were co-cultured for 6 days with CD4+CD25+ depleted PDT cells (p<0.001). Addition of anti-IL-10 monoclonal antibody (mAb) to the co-culture (PDT-treated cells with cGVHD cells) resulted in a 3-fold decrease in the inhibition of cGVHD cell proliferation mediated by PDT-treated cells (p<0.01) and a 1.5-fold decrease when anti-TGF-β mAb was added to the co-culture (p<0.05). In conclusion, our results demonstrate that TH9402 PDT not only eliminates activated T cells, but preserves Tregs, with the functional ability to inhibit residual alloreactive cGVHD cells. This inhibitory effect requires live effector Tregs, secretion of IL-10 and TGF-β expression. With such dual effector mechanisms, photopheresis using TH9402 should translate into improved treatment efficacy and enhanced quality of life for patients with chronic GVHD.

Role of CD28 in Acute Graft-Versus-Host Disease

Blood ◽  
1998 ◽  
Vol 92 (8) ◽  
pp. 2963-2970 ◽  
Author(s):  
Xue-Zhong Yu ◽  
Paul J. Martin ◽  
Claudio Anasetti
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Mhc Class I ◽  
Graft Versus Host Disease ◽  
Interleukin 2 ◽  
Class I ◽  
Host Disease ◽  
Cd8 Cells ◽  
Graft Versus Host

Because CD28-mediated T-cell costimulation has a pivotal role in the initiation and maintenance of T-cell responses, we tested the hypothesis that CD28 is critical for the development of graft-versus-host disease (GVHD). We compared the in vivo effects of CD28−/− T cells transplanted from B6 donor with the CD28 gene deleted by homologous recombination with those of CD28+/+ T cells transplanted from wild-type C57BL/6 (B6) donor. Fifty million CD28−/− or CD28+/+ splenocytes from B6 mice were transplanted into unirradiated (B6 × DBA/2)F1 (BDF1) recipients. Unlike CD28+/+, CD28−/− T cells from B6 mice had lower levels of proliferation and interleukin-2 production, had a limited ability to generate cytotoxic T lymphocytes against the recipient, and did not induce immune deficiency, despite survival in the recipient for at least 28 days. The ability to prevent rejection was reduced by the absence of CD28, because as many as 1.0 × 107 CD28−/− CD8+ cells were needed to prevent rejection of major histocompatibility complex (MHC) class-I incompatible marrow in sublethally irradiated (550 cGy) bm1 recipients, whereas 8.0 × 105 CD28+/+CD8+ T cells were sufficient to produce a similar effect, indicating that CD28 on donor CD8+ cells helps to eliminate host immunity. Two million CD4+CD28−/− or CD28+/+ T cells were transplanted into sublethally irradiated (750 cGy), MHC class-II incompatible (B6 × bm12)F1 recipients. With CD28−/−cells, 44% of the recipients died at a median of 20 days compared with 94% at a median of 15 days with CD28+/+ cells (P < .001). Two million CD8+CD28−/− or CD28+/+ T cells were transplanted into sublethally irradiated (750 cGy), MHC class-I incompatible (B6 × bm1) F1 recipients. With CD28−/−cells, 25% of the recipients died at a median of 41 days compared with 100% at a median of 15 days with CD28+/+ cells (P < .001). (B6 × bm12)F1 and (B6 × bm1)F1 mice surviving after transplantation of CD28−/− cells recovered thymocytes, T cells, and B cells in numbers and function comparable with that of irradiation-control F1 mice. We conclude that CD28 contributes to the pathogenesis and the severity of GVHD. Our results suggest that the severity of GVHD could be decreased by the administration of agents that block CD28 function in T lymphocytes. © 1998 by The American Society of Hematology.

Sign in / Sign up

Export Citation Format

Share Document