Compared to naive T cells, differentiated T cells are thought to be less dependent on CD28 costimulation for full activation. To revisit the role of CD28 costimulation in mouse T cell recall responses, we adoptively transferred in vitro generated OT-II T helper (Th) 1 cells into C57BL/6 mice (Thy1.2+) and then either blocked CD28–ligand interactions with Fab fragments of the anti-CD28 monoclonal antibody (mAb) E18 or deleted CD28 expression using inducible CD28 knock-out OT-II mice as T cell donors. After injection of ovalbumin protein in adjuvant into the recipient mice we observed that systemic interferon (IFN)γ release strongly depended on CD28 costimulation of the Th1 cells, while secondary clonal expansion was not reduced in the absence of CD28 costimulation. For human memory CD4+ T cell responses we also noted that cytokine release was reduced upon inhibition of CD28 costimulation. Together, our data highlight the so far underestimated role of CD28 costimulation for the reactivation of fully differentiated CD4+ T cells.
BackgroundSterile inflammation is a substantial element of post-stroke pathophysiology with the determination of autoimmunity versus tolerance being one of its most important aspects. It is believed that this determination is initiated relatively early after stroke onset by clearing macrophages and migratory dendritic cells (DC). However, the phenotypic differentiation of macrophages and DC is intricate particularly in the disease context. Here, we utilized a set of surface markers used in mucosal immunity research to investigate the involvement of macrophages and DC subpopulations in post-stroke inflammation in mice.FindingsPhotothrombotic stroke induced a significant increase of lineage (CD3, B220, Ly6G and CD49b) negative CD11b+ cells in the brain primarily consisting of F4/80+ macrophages and, to a lesser extent, F4/80-/CD11c-/CD11b+ monocytes and F4/80-/CD11c+ DC. The latter could be differentiated into the classical migratory DC subpopulations (CD11b+ and CD103+), but no CD4 or CD8+ DC were found. Finally, stroke caused a significant increase of CD11b/CD103 double-positive DC in the affected brain hemisphere.ConclusionsThe surface marker combination used in this study allowed a phenotypic differentiation of macrophages and DC subpopulations after stroke, thus providing an important prerequisite to study post-stroke immunity and tolerance.
Acute graft-versus-host disease (aGvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell plus T cell transplantation (allo-HSCT). In this study, we investigated the requirement for CD28 co-stimulation of donor CD4+ conventional (CD4+CD25−Foxp3−, Tconv) and regulatory (CD4+CD25+Foxp3+, Treg) T cells in aGvHD using tamoxifen-inducible CD28 knockout (iCD28KO) or wild-type (wt) littermates as donors of CD4+ Tconv and Treg. In the highly inflammatory C57BL/6 into BALB/c allo-HSCT transplantation model, CD28 depletion on donor CD4+ Tconv reduced clinical signs of aGvHD, but did not significantly prolong survival of the recipient mice. Selective depletion of CD28 on donor Treg did not abrogate protection of recipient mice from aGvHD until about day 20 after allo-HSCT. Later, however, the pool of CD28-depleted Treg drastically declined as compared to wt Treg. Consequently, only wt, but not CD28-deficient, Treg were able to continuously suppress aGvHD and induce long-term survival of the recipient mice. To our knowledge, this is the first study that specifically evaluates the impact of CD28 expression on donor Treg in aGvHD. Moreover, the delayed kinetics of aGvHD lethality after transplantation of iCD28KO Treg provides a novel animal model for similar disease courses found in patients after allo-HSCT.
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Donor lymphocyte infusions together with allogeneic hematopoietic stem cell transplantation are routinely used as second-line treatment for hematological malignancies. Mature T cells in the graft crucially mediate a graft versus leukemia (GvL) response, but also attack healthy tissues in the recipient leading to potentially life-threatening acute graft versus host disease. Using inducible CD28 knockout C57BL/6 mice as T-cell donors, we have now assessed whether CD28 costimulation of donor CD4 + and/ or CD8 + T cells is required for an efficient GvL effect after allogeneic T-cell transplantation into BALB/c recipients. Our results show that CD28 costimulation of donor CD8 + cytotoxic, but not CD4 + helper, T cells was dispensable for curing mice from the BCL-1 lymphoma. Therefore, donor lymphocyte infusion treated lymphoma-bearing BALB/c recipient mice showed enhanced long-term survival when receiving CD28-deficient as compared to wild-type donor CD8 + T cells together with wild-type conventional and regulatory CD4 + T cells. The same was observed when donor CD8 + and conventional and regulatory CD4 + T cells were CD28 deficient. Our data, thus, suggest that systemic CD28 blockade, for example, with the drug FR104 might also reduce acute graft versus host disease in patients after allogeneic hematopoietic stem cell transplantation, while maintaining the protective GvL response.Keywords: Acute graft versus host disease r Graft versus leukemia effect r CD28 costimulation r CD8 + T cells r CD4 + T cells Additional supporting information may be found online in the Supporting Information section at the end of the article. versus leukemia [GvL] effect) [1]. They may, however, cause lethal acute graft versus host disease (aGvHD) [2]. Currently, standard prophylaxis and therapy for aGvHD [3] also impairs the GvL effect and enhances the risk of tumor recurrence. Thus, novel strategies are needed that prevent severe aGvHD but maintain the GvL effect. Interfering with the function of CD28, a costimulatory molecule on T cells, is a promising approach to achieve this therapeutic goal. Activation of T cells in the absence of CD28 costimulation induces anergy, one important mechanism of peripheral tolerance [4]. However, the requirement for CD28
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