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J A Bluestone

Publications and source records attributed to J A Bluestone.

At least 91 records · Page 5Linked to original sources
PubMed1996

TCR-gamma delta cells in CD3 zeta-deficient mice contain Fc epsilon RI gamma in the receptor complex but are specifically unresponsive to antigen.

Unlike TCR-alpha beta cells, TCR-gamma delta cells express a distinct member of the zeta family, the gamma-chain of Fc epsilon RI (Fc epsilon RI gamma) within the TCR complex. To study the role of the Fc epsilon RI gamma-chain in TCR-gamma delta cells, a TCR-gamma delta transgenic mouse (G8) has been crossed with CD3 zeta-chain-deficient mice (G8.zeta-/-). Thy-1+ spleen and lymph node cells of these animals expressed low levels of CD3/TCR. These results suggested that the zeta-chain is required for effective TCR transport to the cell surface. In contrast, intraepithelial TCR-gamma delta cells of G8.zeta-/- mice expressed high levels of TCR. Immunoprecipitation with anti-CD3 showed that Fc epsilon RI gamma-chains were associated with the TCR complex in T cells isolated from zeta-deficient mice. Although the Fc epsilon RI gamma-expressing T cells proliferated in response to stimulation by TCR-specific Abs including anti-CD3 epsilon, anti-pan gamma delta, and anti-V gamma 2 mAb, the G8.zeta-/- T cells did not respond to the G8-specific Ag (T10b), anti-Thy-1 mAb, or Con A. The unresponsiveness to the Ag was not due to the reduced TCR expression, because intraepithelial TCR-gamma delta cells from the zeta-deficient mice did not respond to Ag. The inability of the G8.zeta-/- T cells to respond to Ag could not be overcome by providing an anti-CD28 costimulatory signal or by adding exogenous rIL-2. Taken together, our data suggest that the Fc epsilon RI gamma-chain associates with the TCR-gamma delta complex in the absence of the zeta-chain, but it is not able to substitute for the zeta-chain for effective transport of TCR to the cell surface or functional responses to Ag.

Animals↗
PubMed1996

Immune deviation of 2C transgenic intraepithelial lymphocytes in antigen-bearing hosts.

The present study examined self-tolerance for T cell receptor (TCR) alpha beta intestinal intraepithelial lymphocytes (iIELs) using the 2C transgenic (Tg) mouse model specific for a peptide antigen (Ag) presented by the class I major histocompatibility complex H-2Ld. Although Tg+ T cells were largely deleted from the periphery of Ag+ mice, equivalent numbers of Tg iIELs were present in Ag+ compared to Ag- mice. Tg iIELs in Ag- mice contained CD8 alpha beta, CD8 alpha alpha, and CD4-CD8- subsets, whereas only CD8 alpha alpha and CD4-CD8- Tg iIEL subsets were detected in Ag+ mice. Analysis of surface markers revealed that Tg iIELs in Ag+ mice expressed decreased levels of Thy-1 and increased CD45R/B220 as compared to Ag- Tg iIELs. In response to activation with exogenous peptide or immobilized anti-TCR mAB, iIELs from Ag- mice proliferated at high levels and produced interleukin (IL)-2 and interferon (IFN)-gamma, while Tg+ iIELs from Ag+ mice proliferated at low levels and failed to produce detectable IL-2 or IFN-gamma. Activation of sorted iIEL subsets from Ag- mice revealed that CD8 alpha alpha and CD4-CD8- subsets produced low levels of IL-2 and IFN-gamma in response to activation with antigen-presenting cells and added peptide or immobilized anti-TCR mAb, while CD8 alpha beta + iIELs responded to endogenous levels of peptide. In response to APC and exogenous peptide, sorted iIEL subsets from Ag+ mice produced IL-2 and IFN-gamma, and proliferated at greatly reduced levels compared to corresponding subsets from Ag- mice. Analysis of cytokine mRNA levels revealed that activation in vitro induced IL-2 mRNA only in Ag-, but not Ag+ iIELs, whereas a high level of IL-4 mRNA induction was detected in Tg+ iIELs from Ag+ mice, and to a lesser degree, from Ag- mice. These data suggest that tolerance for Tg+ iIELs resulted in the deletion of CD8 alpha beta + subsets and the persistence of Tg+ iIEL subsets with decreased sensitivity to endogenous levels of self-peptide. A comparison of the cytokine profiles expressed by Tg+ iIEL subsets in Ag- and Ag+ mice suggested that tolerance induction had involved the functional deviation of cells from TC1 (T helper-1-like) to a less inflammatory TC2 (T helper-2-like) phenotype capable of mediating humoral immune responses in the mucosa.

Animals↗
PubMed1996

CTLA-4: a negative regulator of autoimmune disease.

CTLA-4, a CD28 homologue expressed on activated T cells, binds with high affinity to the CD28 ligands, B7-1 (CD80) and B7-2 (CD86). This study was designed to examine the role of CTLA-4 in regulating autoimmune disease. Murine relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE) is a demyelinating disease mediated by PLP139-151-specific CD4+ T cells in SJL/J mice. Anti-CTLA-4 mAbs (or their F(ab) fragments) enhanced in vitro proliferation and pro-inflammatory cytokine production by PLP139-151-primed lymph node cells. Addition of either reagent to in vitro activation cultures potentiated the ability of T cells to adoptively transfer disease to naive recipients. In vivo administration of anti-CTLA-4 mAb to recipients of PLP139-151-specific T cells resulted in accelerated and exacerbated disease. Finally, anti-CTLA-4 treatment of mice during disease remission resulted in the exacerbation of relapses. Collectively, these results suggest that CTLA-4 mediates the downregulation of ongoing immune responses and plays a major role in regulating autoimmunity.

Abatacept↗
PubMed1996

CTLA-4 ligation blocks CD28-dependent T cell activation.

CTLA-4 is a CD28 homologue believed to be a negative regulator of T cell function. However, the mechanism of this downregulatory activity is not well understood. The present study was designed to examine the effect of CTLA-4 ligation on cytokine production, cell survival, and cell cycle progression. The results demonstrate that the primary effect of CTLA-4 ligation is not the induction of apoptosis. Instead, CTLA-4 signaling blocks IL-2 production, IL-2 receptor expression, and cell cycle progression of activated T cells. Moreover, the effect of CTLA-4 signaling was manifested after initial T cell activation. Inhibition of IL-2 receptor expression and cell cycle progression was more pronounced at late (72 h) time points after initial activation. The effects of anti-CTLA-4 mAbs were most apparent in the presence of optimal CD28-mediated costimulation consistent with the finding that CTLA-4 upregulation was CD28-dependent. Finally, the addition of exogenous IL-2 to the cultures restored IL-2 receptor expression and T cell proliferation. These results suggest that CTLA-4 signaling does not regulate cell survival or responsiveness to IL-2, but does inhibit CD28-dependent IL-2 production.

Abatacept↗
PubMed1996

Murine gamma/delta-expressing T cells affect alloengraftment via the recognition of nonclassical major histocompatibility complex class Ib antigens.

T cells with antidonor specificities have been isolated from human recipients experiencing graft rejection after allogeneic bone marrow transplantation (BMT). Partial T-cell depletion of unrelated BM grafts with an anti- T-cell receptor (TCR) monoclonal antibody (MoAb) directed against the TCR alpha/beta heterodimer have shown that the incidence of graft-versus-host disease is low and that the incidence of durable engraftment is high. These studies suggest either that the number of residual TCR alpha/beta+ cells was sufficient to permit alloengraftment or that the preservation of cells other than TCR alpha/beta+ cells was beneficial for engraftment. With respect to the latter, one such candidate cell is the TCR gamma/delta+ T cell. Because no studies have specifically examined whether TCR gamma/delta+ cells might be capable of eliminating BM-derived hematopoietic cells, we established a new graft rejection model system in which transgenic (Tg) H-2d mice (termed G8), known to express gamma/delta heterodimers on high proportion of peripheral T cells, were used as BMT recipients. These Tg TCR gamma/delta+ cells respond vigorously to target cells that express the nonclassical major histocompatibility complex (MHC) class lb region gene products encoded in H-2T region of H-2T(b)+ strains. G8 Tg mice were used as recipients for C57BL/6 (B6: H-2(b); H-2T(b)) T-cell-depleted (TCD) donor BM. We show that G8 Tg (H-2(d), H-2T(d)) mice are potent mediators of B6 BM graft rejection and that the rejection process was inhibited by anti-TCR gamma/delta MoAbs. In contrast, BM from a B6 congenic strain that expresses the H-2T(a) allele, B6.A-Tl(a)/BoyEg, was readily accepted, suggesting that H-2T antigens on repopulating donor BM cells are the targets of host graft rejecting T cells that express the TCR gamma/delta heterodimer. PB chimerism studies were performed at > or = 1.5 months post-BMT using TCD BM from severe combined immunodeficient allogeneic donors, which is highly susceptible to rejection by the host. The addition of donor G8 TCR gamma/delta+ cells to TCD donor BM was shown to significantly increase alloengraftment in B6 recipients. These results show that (1) host TCR gamma/delta+ cells can reject repopulating donor cells, presumably by responding to nonclassical MHC class lb gene products expressed on BM-derived hematopoietic progenitor cells; and (2) donor TCR gamma/delta+ cells can facilitate the alloengraftment of rigorously TCD donor BM.

Animals↗
PubMed1996

In vivo administration of anti-murine CD3 monoclonal antibody induces selective, long-term anergy in CD8+ T cells.

The purpose of this study was to determine the short-term and long-term effects of repeated daily administration of low dose anti-CD3 monoclonal antibody (mAb) on CD4+ and CD8+ T cell number and function. Daily (7 days) administration of low doses (5 microg) of mitogenic (whole) or nonmitogenic (F(ab')2, fragments) anti-CD3 mAb resulted in depletion of CD4+ and CD8+ T cells in both lymph node and spleen that, in the case of whole mAb, persisted for several months in thymectomized animals. CD3+ cells obtained from thymectomized animals treated with whole but not F(ab')2 fragments of anti-CD3 mAb demonstrated decreased proliferation to anti-CD3 mAb in vitro (on a per cell basis as compared with control animals). Although purified CD4+ cells from animals treated with whole mAb demonstrated only slightly decreased proliferative responses to anti-CD3 mAb in vitro, purified CD8+ cells demonstrated an almost complete loss of their proliferative response. Studies in thymectomized animals demonstrated that the profound CD8+ cell hyporesponsiveness persisted for at least 5 months after anti-CD3 treatment. These effects were not observed in nonthymectomized animals, however, suggesting that recovery of CD8+ T cell function is caused by repopulation of lymphoid organs by thymic-derived CD8+ T cells. Additional studies with purified CD8+ cells from anti-CD3 mAb-treated animals indicated that the hyporesponsiveness was not caused by alterations in T cell receptor (TCR) expression. However, proliferative responses of anergic CD8+ T cells to phorbol ester and ionomycin were comparable to those of control CD8+ T cells. After in vitro stimulation, CD8+ cells from anti-CD3 treated animals did not produce interleukin (IL)-2, and although they retained their ability to upregulate IL-2 receptor expression (albeit reduced by about 50% compared with CD8+ cells from control animals), proliferative responses were not restored by addition of exogenous IL-2. In addition to IL-2 receptor expression, CD8+ cells from anti-CD3-treated animals also demonstrated an ability to upregulate CD44 and LFA-1 expression upon reexposure to anti-CD3 mAb in vitro. In conclusion, treatment with daily administration of low doses of whole or F(ab')2 fragments of anti-murine CD3 mAb induces significant T cell depletion in secondary lymphoid organs and does not seem to alter CD4+ proliferative responses in vitro, but whole mAb (and not F(ab')2 fragments) profoundly suppresses CD8+ proliferative responses. The profound hyporesponsiveness of CD8+ T cells induced by whole anti-murine CD3 mAb (1)persists for at least persists for at least several months, (2) is characterized by decreased IL-2 production and responsiveness to IL-2, and (3) recovery of CD8+ cell function is likely mediated by repopulation of lymphoid organs by thymic-derived CD8+ cells.

Animals↗
PubMed1996

CD28 expression is not essential for positive and negative selection of thymocytes or peripheral T cell tolerance.

Thymocyte development requires positive selection of clones that can recognize Ag presented by MHC molecules and negative selection of clones that are self-reactive. However, the costimulatory signals required for negative selection and cell death, or positive selection and the transition to the peripheral lymphoid system, are not well understood. Many molecular interactions that are important for T cell activation have also been found to play a role in thymocyte development. The importance of the CD28/B7 interaction in the activation of mature T cells and recent observations that CD28 may play a role negative selection of developing CD4+CD8+ thymocytes suggest that CD28 may also be involved in development and maintenance of T cell tolerance. CD28-deficient mice were crossed to alpha beta and gamma delta TCR transgenic as well as H-2k Mlsc-bearing animals and were used to address the role of CD28 in positive and negative selection of developing T cells. The CD28-deficient animals demonstrated no obvious deficiency in either positive or negative selection of developing thymocytes. However, when mixed bone marrow chimeras were created with cells derived from both CD28-deficient and wild-type mice, the CD28+ T cells had a selective advantage over the CD28-deficient T cells. Therefore, it appears that CD28, although not essential for the selection of T cells during development, may allow for additional signals that increase the efficiency of selection and/or expansion of peripheral T cell populations.

Animals↗
PubMed1996

IL-15 is a novel growth factor for murine gamma delta T cells induced by Salmonella infection.

We have previously shown evidence for the early recruitment of gamma delta T cells during the disease course of primary infections with Listeria monocytogenes or Salmonella choleraesuis in mice. Since gamma delta T cells at this stage of the disease do not produce IL-2, the growth factor for the gamma delta T cells remains unknown. IL-15 is a novel cytokine that uses beta- and gamma-chain of IL-2R for signal transduction, and is produced by activated monocytes/macrophages. In this study, we investigated the proliferative activity of IL-15 for gamma delta T cells appearing after primary infection with S. choleraesuis 31N-1. The gamma delta T cells, which expressed beta- and gamma-chains of IL-2R, proliferated in the presence of rIL-15 and produced appreciable levels of gamma-IFN and IL-4. Addition of anti-IL-2R beta mAb significantly inhibited the IL-15-induced proliferation of the gamma delta T cells. Furthermore, the gamma delta T cells produced gamma-IFN in response to monocyte/macrophage cell line, J774A.1 infected with S. choleraesuis, which expressed an abundant level of IL-15 mRNA. This cytokine production was inhibited significantly by anti-IL-15 Ab. Taken together, these results suggest that IL-15 derived from infected macrophages may contribute to the early activation of gamma delta T cells during salmonellosis.

Animals↗
PubMed1996

Lethal murine graft-versus-host disease induced by donor gamma/delta expressing T cells with specificity for host nonclassical major histocompatibility complex class Ib antigens.

Although T-cell receptor (TCR) alpha/beta expressing cells have a well-known role in graft-versus-host disease (GVHD) generation, the role of TCR gamma/delta expressing cells in this process has remained unclear. To elucidate the potential function of TCR gamma/delta cells in GVHD, we have used transgenic (Tg) H-2d mice (termed G8) that express gamma/delta heterodimers on a high proportion of peripheral T cells. In vitro, G8 Tg gamma/delta T cells proliferate to and kill C57BL/6 (B6) (H-2b) which express gene products (T10b and T22b) from the nonclassical major histocompatibility complex (MHC) class Ib H-2T region. The infusion of G8 Tg (H-2Td) TCR gamma/delta cells into lethally irradiated [900 cGy total body irradiation (TBI)] B6 (H-2b) mice resulted in the generation of lethal GVHD characterized histologically by destruction of the spleen, liver, lung, and colon. Lethal GVHD was prevented by the injection of anti-TCR gamma/delta monoclonal antibodies. Immunohistochemical analysis of B6 recipients post-bone marrow transplantation (BMT) confirmed that G8 Tg TCR gamma/delta cells infiltrated GVHD target tissues (skin, liver, colon, and lung) and were absent in recipients treated with anti-TCR gamma/delta monoclonal antibodies (MoAbs) but not anti-CD4 plus anti-CD8 MoAbs. In contrast, injection of TCR gamma/delta+ cells into irradiated (900 cGy TBI) B6.A-TIaa BoyEg mice that do not express either T10b or T22b did not induce lethal GVHD. Similarly, in a different GVHD system in which sublethal irradiation without bone marrow (BM) rescue was used, B6 but not B6.A-TIaa/BoyEg mice were found to be susceptible to TCR gamma delta+ cell mediated GVHD-induced lethality characterized by an aplasia syndrome. These results demonstrate that TCR gamma/delta cells have the capacity to cause acute lethal GVHD in mice and suggest that nonclassical MHC class Ib gene products expressed on GVHD target organs are responsible for G8 Tg TCR gamma/delta+ cell mediated lethality.

Animals↗
PubMed1996

Therapeutic effectiveness of the immunity elicited by P815 tumor cells engineered to express the B7-2 costimulatory molecule.

It is well accepted that inoculation of B7-1-transfected tumor cells into normal mice leads to tumor rejection and subsequent resistance to challenge. However, the effectiveness of B7-2-transfected tumor cells in eliciting protective antitumor immunity is less clear. Here we show that B7-2-transfected P815 tumor cells (B7-2+) are as effective as B7-1-transfected P815 tumor cells (B7-1+) in eliciting protective immunity in normal DBA/2 mice. In addition, B7-2+ cells were found to be at least as effective as B7-1+ cells retarding tumor progression when admixed with parental P815 tumor cells prior to inoculation into normal mice. Moreover, the B7-2+ cells and the B7-1+ cells were equivalent in their ability to retard tumor growth when administered peritumorally into mice bearing established (approx. 3 mm in diameter) parental P815 tumors. Finally, P815 tumor cells infected with a recombinant replication-defective adenovirus encoding the murine B7-2 gene were effective in retarding the growth of established parental P815 tumors. Thus, B7-1 and B7-2 are comparable in terms of their ability to stimulate the generation of tumor-eradicating immunity in normal mice as well as in mice bearing established parental tumors. Moreover, adenovirus vectors can be used to generate B7-2-expressing tumor cells effective in the immunotherapy of established parental tumors.

Adenoviridae↗
PubMed1996

CD28/B7 regulation of Th1 and Th2 subsets in the development of autoimmune diabetes.

CD28 ligation delivers a costimulatory signal important in T cell activation. This study demonstrates that the disruption of the CD28/B7 pathway early in the nonobese diabetic mouse strain, using CD28-/- and CTLA41g transgenic mice, promoted the development and progression of spontaneous autoimmune diabetes. Functional analyses of T cells isolated from CD28-deficient mice demonstrated that the GAD-specific T cells produced enhanced Th1-type cytokines (IL-2 and IFN gamma) and diminished Th2-type cytokine, IL-4. Moreover, there was a significant decrease in serum levels of anti-GAD antibodies of the IgG1 isotype consistent with a profound suppression of Th2-type responses in these animals. Thus, the early differentiation of naive diabetogenic T cells into the Th2 subset is dependent upon CD28 signaling and extends our understanding of the importance of Th1/Th2 balance in the regulation of this spontaneous autoimmune disease.

Abatacept↗
PubMed1996

CD28/B7 system of T cell costimulation.

T cells play a central role in the initiation and regulation of the immune response to antigen. Both the engagement of the TCR with MHC/Ag and a second signal are needed for the complete activation of the T cell. The CD28/B7 receptor/ligand system is one of the dominant costimulatory pathways. Interruption of this signaling pathway with CD28 antagonists not only results in the suppression of the immune response, but in some cases induces antigen-specific tolerance. However, the CD28/B7 system is increasingly complex due to the identification of multiple receptors and ligands with positive and negative signaling activities. This review summarizes the state of CD28/B7 immunobiology both in vitro and in vivo; summarizes the many experiments that have led to our current understanding of the participants in this complex receptor/ligand system; and illustrates the current models for CD28/B7-mediated T cell and B cell regulation. It is our hope and expectation that this review will provoke additional research that will unravel this important, yet complex, signaling pathway.

Animals↗
PubMed1996

Costimulation and its role in organ transplantation.

Antigen-specific T-cell activation depends initially on the interaction of the T-cell receptor with peptide/major histocompatibility complex (MHC). In addition, a costimulatory signal, mediated by distinct cell surface accessory molecules such as CD28, is required for complete T-cell activation. One essential element of the CD28 costimulatory system that makes it an attractive target for immunotherapy is the selective effect of CD28 antagonists on activated T cells. Only cells encountering antigen presenting cells (APCs) without the appropriate CD28 ligand will be rendered functionally inactive as desired for any next-generation immuno-suppressive drug. This brief review will focus on the role of CD28/B7 interactions in regulating organ graft rejection. In vitro and in vivo studies will describe the use of a soluble fusion protein antagonist of CD28/B7 (CTLA-4Ig), anti-B7 MAbs, and genetically altered CD28 "knockout" mice to study immune responses. The studies suggest that: 1) CTLA-4Ig induces long-term, antigen-specific unresponsiveness in vivo; 2) two distinct ligands for CD28, B7-1 and B7-2, are differentially regulated during immune responses; and 3) both B7-1 and B7-2 costimulatory molecules are active, in vivo, although B7-2 plays a clearly dominant role in murine allograft rejection.

Abatacept↗
PubMed1995

Inhibition of transplant rejection following treatment with anti-B7-2 and anti-B7-1 antibodies.

Antigen-specific T cell activation depends initially on the interaction of the T cell receptor (TCR) with peptide/MHC. In addition, a costimulatory signal, mediated by distinct cell surface accessory molecules, is required for complete T cell activation leading to lymphokine production and proliferation. CD28 has been implicated as the major receptor on T cells responsible for delivering the costimulatory signal. Although two distinct ligands for CD28, B7-1 and B7-2, have been identified on antigen-presenting cells (APC), the co-stimulatory role of each molecule during a physiological immune response remains unresolved. In the present study, the relative roles of B7-1 and B7-2 interactions were evaluated in an allogeneic pancreatic islet transplant setting. In isolation, anti-B7-2 mAbs and, to a much lesser degree, anti-B7-1 mAbs suppressed T cell proliferative responses to allogeneic islets or splenic APC in vitro. Maximal inhibition of the allogeneic response was observed using a combination of the anti-B7-1 and anti-B7-2 mAbs. Administration of anti-B7-2 but not anti-B7-1 mAbs prolonged C3H allograft survival in B6 recipients, with a combination of both mAbs significantly prolonging rejection beyond either mAb alone. The immunosuppressive effects of the in vivo mAb treatment were not manifested in in vitro analyses as T cells isolated from suppressed mice responded normally to allogeneic stimuli in terms of both proliferation and lymphokine production. However, combined mAb therapy in vivo selectively delayed CD4+ T lymphocyte infiltration into the graft. These data suggest that both B7-1 and B7-2 costimulatory molecules are active in vivo, although B7-2 plays a clearly dominant role in this allograft model. The mechanism of immune suppression in vivo remains unresolved but may occur at sites distinct from the allograft.

Abatacept↗
PubMed1995

Functional expression and recognition of nonclassical MHC class I T10b is not peptide-dependent.

Studies of classical and nonclassical MHC class I molecules have shown that unique peptides are associated and functionally recognized by alloreactive T cells. We have recently shown that an alloreactive TCR-gamma delta cell recognizes a nonclassical MHC molecule, T10b. However, T cell recognition of this glycoprotein did not appear to require typical peptide recognition based on studies using transporter-defective mutant cell lines. In the current study, we have analyzed in detail, the role of peptide in T10b expression and recognition. The findings reveal that the recognition of the nonclassical MHC molecule by TCR-gamma delta cells is independent of species, tissue type, both the class I and class II Ag processing and presentation pathways, or the presence of peptides. In fact, biochemical analysis of the T10b chimeric molecule, T10b/Ld, transfected into CHO cells using radiolabeled [3H]leucine, HPLC, and mass spectrometry suggest that peptides are not associated with this nonclassical class I molecule. Therefore, some class I molecules, e.g., T10b, do not associate with polymorphic peptides typical of classical MHC class I molecules and can be expressed in the absence of peptides on the cell surface in a functionally active form.

Animals↗
PubMed1995

Ly-6C is a marker of memory CD8+ T cells.

This study examined long-term phenotypic and functional effects of TCR ligation in vivo. Flow cytometric analysis of T cells from mice treated with anti-CD3 revealed an increase in CD44 expression in both the CD4+ and CD8+ populations. The phenotypic changes were a result of TCR engagement, because treatment with staphylococcal enterotoxin B (SEB) resulted in a preferential increase in CD44 expression on the SEB-reactive V beta 8 T cells. In addition, the percentage of cells expressing Ly-6C increased among the CD8+ subset after anti-CD3 treatment and in the V beta 8+ CD8+ subset after treatment with SEB. Finally, the TCR transgenic (Tg) mouse strain 2C was used to confirm that the phenotypic changes can be induced by exposure to a physiologic ligand (H-2Ld). Before treatment, nearly all of the Tg+CD8+ cells were CD44low/Ly-6C-. Tg+ peritoneal exudate T cells isolated from mice challenged with P815 cells (H-2Ld) up-regulated Ly-6C and secreted higher levels of IFN-gamma on a per Tg+ CD8+ T cell basis after treatment. Taken together, these data indicate that in vivo TCR/CD3 engagement results in phenotypic and functional changes in T cells. Furthermore, Ly-6C expression correlates with an increase in IFN-gamma production after antigenic stimulation of CD8+ T cells, suggesting that it is a "memory" marker that correlates with Ag-specific functional changes in CD8+ T cells.

Animals↗
PubMed1995

Antigen-dependent clonal expansion of a trace population of antigen-specific CD4+ T cells in vivo is dependent on CD28 costimulation and inhibited by CTLA-4.

The importance of CD28 costimulation to a primary T cell response in vivo was assessed in an adoptive transfer system where a small population of peptide-specific CD4+ TCR transgenic T cells can be physically tracked. Ag-dependent clonal expansion of the transgenic T cells in draining lymph nodes was blocked by cyclosporin A and required a CD28 signal that was completely inhibited by CTLA-4-Ig or a combination of anti-B7-1 and anti-B7-2 mAbs, but not by either Ab alone. In vivo treatment with the combination of anti-B7-1 and anti-B7-2 mAbs also blocked conversion of the Ag-specific T cells to the activated phenotype. In contrast, anti-CTLA-4 Fab greatly enhanced the in vivo clonal expansion of the Ag-specific T cells. These results suggest that Ag-driven proliferation and phenotype conversion of naive CD4+ T cells is dependent on CD28-derived signals and is inhibited by CTLA-4.

Abatacept↗