Donor CD4 Cells Research Articles

Minimal bystander activation of CD8 T cells during the virus-induced polyclonal T cell response.

Acute infections with viruses such as lymphocytic choriomeningitis virus (LCMV) are associated with a massive polyclonal T cell response, but the specificities of only a small percentage of these activated T cells are known. To determine if bystander stimulation of T cells not specific to the virus plays a role in this T cell response, we examined two different systems, HY-specific T cell receptor (TCR)-transgenic mice, which have a restricted TCR repertoire, and LCMV-carrier mice, which are tolerant to LCMV. LCMV infection of HY-transgenic C57BL/6 mice induced antiviral CTLs that lysed target cells coated with two of the three immunodominant epitopes previously defined for LCMV (glycoprotein 33 and nucleoprotein 397). Although LCMV-induced cytotoxic T lymphocytes (CTLs) from C57BL/6 mice could lyse uninfected H-2(k) and H-2(d) allogeneic targets, LCMV-induced CTLs from HY mice lysed only the H-2(k)-expressing cells. The HY mice generated both anti-H-2(k) and anti-H-2(d) CTL in mixed leukocyte reactions, providing evidence that the generation of allospecific CTLs during acute LCMV infection is antigen specific. During the LCMV infection there was blastogenesis of the CD8+ T cell population, but the HY-specific T cells (as determined by expression of the TCR-alpha chain) remained small in size. To examine the potential for bystander stimulation under conditions of a very strong CTL response, T cell chimeras were made between normal and HY mice. Even in the context of a normal virus-induced CTL response, no stimulation of HY-specific T cells was observed, and HY-specific cells were diluted in number by day 9 after infection. In LCMV-carrier mice in which donor and host T cells could be distinguished by Thy1 allotypic markers, adoptive transfer of LCMV-immune T cells into LCMV-carrier mice, whose T cells were tolerant to LCMV, resulted in activation and proliferation of donor CD8 cells, but little or no activation of host CD8 cells. These results support the hypothesis that the massive polyclonal CTL response to LCMV infection is virus-specific and that bystander activation of non-virus-specific T cells is not a significant component of this response.

Attenuated parasites and the development of an erythrocytic-stage vaccine

Asexual-stage vaccine candidates may be identified by recognition of antibodies to them in the sera of naturally immune individuals. Once identified, recombinant molecules expressing the relevant antigen can be produced, although such recombinant molecules only seem to be effective at inducing immunity if mixed with adjuvant. More information is needed about the role of antibodies in immunity to malaria. In an animal model, that of Plasmodium berghei in mice, a fairly effective immune response can be produced by inoculating mice with live, proliferating parasites and then keeping the infections subclinical, by drug treatment, for 5 weeks. However, the resultant ‘immune1 individuals carry small numbers of parasites despite the presence of antibody (premunition). Repeated challenge infections are limited by the hosts’ immune responses but sterile immunity is not observed, The immunity that is established only fades in the absence of the parasite, In contrast, inoculation with preparations of disrupted parasites, which do not seem to contain all the antigenic information of the living parasites, do not lead to an immune response which limits parasitaemias. These observations may be the result of antigenic variation. Immunity induced in mice by live, attenuated parasites (but not by extracts) protects against challenge with virulent parasites. Immunity against the attenuated but not the virulent parasite can be transferred by inoculating naive mice with spleen cells from the immunized mice. The mice given spleen cells can then be protected against the virulent parasite by challenge with proliferating, attenuated parasites (but not with extracts). Immune B cells from the immune donor and non-immune CD4 cells in the naive recipient are essential for transfer of immunity.

Association between enhanced TH2/TH1 cytokine profile and donor T-cell chimerism following total lymphoid irradiation

Total lymphoid irradiated (TLI) mice develop antigen specific tolerance if the initial antigen exposure occurs shortly after the completion of TLI. We injected TLI-treated mice with semiallogeneic donor cells at 2, 7, or 28 days after completing TLI and determined the levels of donor CD4 and CD8 cells 5 to 7 weeks after TLI treatment. The level of chimerism correlated with the timing of the initial alloantigen exposure. Donor CD4 and CD8 cells were noted only in day 2 or 7 injected mice. Because donor cell chimerism suggested increased in vivo survival of donor cells, we used the level of donor cell chimerism as a surrogate marker for tolerance to examine the relationship between the development of tolerance and enhanced Th2/Th1 cytokine responses to donor antigen. Increased levels of donor CD4 and CD8 cells in the TLI-treated mice was associated with increased Th2/Th1 cytokine production and decreased CTL activity to donor antigen in vitro. Higher Th2/Th1 cytokine levels also correlated with lower CTL activity. The results indicate that the increased production of Th2/Th1 may function to enhance survival of donor cells in TLI-treated mice and suggest that tolerance induction after TLI treatment involves immunoredirection.

Contributions of donor CD4 and CD8 cells to liver injury during murine graft-versus-host disease.

We have determined the capacity of donor CD4 and CD8 T cells to mediate liver injury in the B10.D2 (donor) into BALB/c (host) chronic graft-versus-host disease (GVHD) model. First, we compared the effects of treating GVHD mice with anti-CD4 or anti-CD8 versus no treatment on the liver histology scores and elevated serum IgE levels in this model. We also examined the abilities of purified donor total T, CD4, and CD8 cells to mediate hepatic GVHD lesions. Anti-CD4 and anti-CD8 treatments caused profound depletion of peripheral CD4+ and CD8+ cells, respectively, and produced a relative enrichment of the CD8+ and CD4+ cells in the liver. Hepatic GVHD lesions and elevated serum IgE concentrations were both suppressed by anti-CD4 treatment. Anti-CD8 treatment had no effect on the severity of hepatic lesions and caused a significant increase in serum IgE levels. Attempts to induce hepatic GVHD with purified donor CD4 and CD8 cells were inconclusive because the onset of liver lesions was delayed and the lesions in both groups were contaminated by the opposite subset. Altogether, our results indicate that both hepatic lesions and elevated serum IgE concentrations in this GVHD model are dependent on donor CD4 cells. Donor CD4 cells mediated hepatic GVHD in the absence of CD8 cells. Donor CD8 cells did not produce hepatic GVHD in the absence of CD4 cells and appeared to be dependent on CD4 cells.

Prevention of Allogeneic Marrow Graft Rejection by Donor T Cells That Do Not Recognize Recipient Alloantigens: Potential Role of a Veto Mechanism

Clinical trials and experimental studies have demonstrated that donor T cells can play a critical role in preventing allogeneic marrow graft rejection. Results of a previous study showed that donor T cells were most effective for preventing rejection when they recognize an alloantigen expressed by recipient T cells and can cause graft-versus-host disease (GVHD). The present study examined models where marrow graft rejection can be prevented by donor T cells that do not recognize host alloantigens and cannot cause GVHD. Donor T cells prevented rejection of major histocompatibility complex (MHC) class I and II-disparate F1 marrow in parental recipients prepared with > or = 800 cGy total body irradiation (TBI) but not in those prepared with < or = 750 cGy TBI. In recipients prepared with high TBI exposures, rejection was mediated entirely by host CD8 cells. With lower TBI exposures, rejection was mediated by host CD4 cells and CD8 cells. These observations suggested the hypothesis that donor T cells prevent rejection mediated by host effectors that recognize donor MHC class I alloantigens but do not prevent rejection mediated by host effectors that recognize donor class II alloantigens. Consistent with this hypothesis, further experiments showed that F1 donor T cells can prevent rejection of MHC class I-disparate marrow in irradiated parental recipients but have no detectable effect on rejection of MHC class II-disparate marrow. We propose that the expression of MHC class I molecules on donor T cells makes it possible for these cells to inactivate the host response against donor class I alloantigens through a veto mechanism, whereas the absence of MHC class II molecules on murine T cells explains why these cells cannot inactivate the host response against donor class II alloantigens. Finally, donor CD4 cells and CD8 cells were equivalently effective for preventing rejection of F1 marrow in parental recipients, suggesting that veto activity is not restricted solely to the CD8 subset of murine T cells. A veto mechanism could enable donor T cells to prevent allogeneic marrow graft rejection without causing GVHD.

Prevention of allogeneic marrow graft rejection by donor T cells that do not recognize recipient alloantigens: potential role of a veto mechanism

Clinical trials and experimental studies have demonstrated that donor T cells can play a critical role in preventing allogeneic marrow graft rejection. Results of a previous study showed that donor T cells were most effective for preventing rejection when they recognize an alloantigen expressed by recipient T cells and can cause graft-versus- host disease (GVHD). The present study examined models where marrow graft rejection can be prevented by donor T cells that do not recognize host alloantigens and cannot cause GVHD. Donor T cells prevented rejection of major histocompatibility complex (MHC) class I and II- disparate F1 marrow in parental recipients prepared with &gt; or = 800 cGy total body irradiation (TBI) but not in those prepared with &lt; or = 750 cGy TBI. In recipients prepared with high TBI exposures, rejection was mediated entirely by host CD8 cells. With lower TBI exposures, rejection was mediated by host CD4 cells and CD8 cells. These observations suggested the hypothesis that donor T cells prevent rejection mediated by host effectors that recognize donor MHC class I alloantigens but do not prevent rejection mediated by host effectors that recognize donor class II alloantigens. Consistent with this hypothesis, further experiments showed that F1 donor T cells can prevent rejection of MHC class I-disparate marrow in irradiated parental recipients but have no detectable effect on rejection of MHC class II-disparate marrow. We propose that the expression of MHC class I molecules on donor T cells makes it possible for these cells to inactivate the host response against donor class I alloantigens through a veto mechanism, whereas the absence of MHC class II molecules on murine T cells explains why these cells cannot inactivate the host response against donor class II alloantigens. Finally, donor CD4 cells and CD8 cells were equivalently effective for preventing rejection of F1 marrow in parental recipients, suggesting that veto activity is not restricted solely to the CD8 subset of murine T cells. A veto mechanism could enable donor T cells to prevent allogeneic marrow graft rejection without causing GVHD.

Donor CD8 cells prevent allogeneic marrow graft rejection in mice: potential implications for marrow transplantation in humans.

Numerous experimental models have demonstrated that graft-vs.-host disease (GVHD) does not occur in irradiation chimeras when the graft does not contain mature, immunocompetent T lymphocytes, but clinical studies have shown that T cell depletion of donor marrow can be associated with a greatly increased risk of graft failure. We have developed a model where engraftment of (C57BL/6J x C3H/HeJ)F1 (B6C3) marrow in 800-cGy-irradiated (BALB/cJ x C57BL/6J)F1 (CB6) recipients depends on the presence of donor T cells in the graft. Recipients transplanted with 5.0 x 10(6) marrow cells depleted of T lymphocytes showed host lymphoid and myeloid reconstitution, whereas recipients transplanted with the same marrow plus 2.5 x 10(5) purified donor T cells showed donor reconstitution. Adding as few as 0.5 x 10(5) CD8-enriched donor T cells to marrow grafts containing 5.0 x 10(6) T cell-depleted donor cells was sufficient to enable donor reconstitution, while surviving recipients transplanted with the same marrow and 0.5-2.5 x 10(5) CD4-enriched donor cells showed only host reconstitution. To address the question of whether donor CD4 cells could facilitate engraftment under conditions where GVHD would not represent a limiting factor, engraftment of bm1 marrow was tested in major histocompatibility complex (MHC) class I-disparate B6.Ly5a recipients. Results indicated that the donor CD8-enriched population was at least fivefold more active than the CD4-enriched population for facilitating allogeneic marrow engraftment in this strain combination. Thus, the lymphokines and MHC class II-specific cytotoxic T cells generated by CD4 cells were relatively ineffective for enhancing engraftment, possibly reflecting the fact that the host T cells that contain effectors responsible for causing rejection do not express MHC class II antigens. The ability of donor CD8 cells to facilitate engraftment could reflect the activity of a cytokine uniquely elaborated after recognition of an MHC class I disparity. More likely, the graft-enhancing effect of donor CD8 cells may result from the generation of MHC class I-specific or class I-restricted cytotoxic T cells that recognize the host CD4 and CD8 cells responsible for causing rejection. The possibility remains that other mechanisms such as veto inactivation of host T cells by donor CD8 cells may also contribute to the graft-enhancing effect.