Helper T cells for cytotoxic T lymphocytes need not be I region restricted

Raulet, David H.; Bevan, Michael J.

doi:10.1084/jem.155.6.1766

Cited by 25 publications

(10 citation statements)

References 45 publications

(57 reference statements)

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“…Mice homozygous for the gld or the lpr mutation develop progressive lymphadenopathy and systemic autoimmune disease. In the C57BL/6 genetic background, these symptoms develop with significantly slower kinetics and decreased severity than in the autoimmuneprone MRL-lpr mice, which, in addition, suffer from arthritis and glomerulonephritis [43]. It is, therefore, remarkable that in the case of PKO-gld mice, the disruption of perforin and Fas ligand leads to severe lymphoproliferation and rapid lethality even in the relatively resistant C57BL/6 genetic background.…”

Section: Discussionmentioning

confidence: 99%

Homeostatic regulation of CD8+ T cells by perforin

1999

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To prevent uncontrolled expansion, the massive proliferation of T cells during an acute immune response has to be followed by controlled deletion. Here we show that similar to Fas, perforin is not only an important effector molecule of cytotoxic T lymphocytes (CTL) but also involved in down‐regulating peripheral T cells. Mice deficient for both the CTL effector molecule perforin and the apoptosis‐inducing Fas ligand spontaneously develop infiltration of highly activated CD8+ T cells in kidney and liver and die between 5 and 12 weeks of age. Injection of staphylococcal enterotoxin B (SEB) into perforin‐deficient mice results in dramatically increased selective expansion and prolonged persistence of CD8+, but not CD4+, SEB‐reactive T cells. Also, secondary immunization of TCR transgenic perforin‐deficient mice with the lymphocytic choriomeningitis virus glycoprotein‐derived epitope peptide leads to an increased proliferation of transgenic CD8+ T cells, that is not explained by failure to deplete professional antigen‐presenting cells. These results point to a novel mechanism of T cell homeostasis in which the acquisition of perforin‐dependent cytotoxic activity regulates the expansion and persistence of CD8+ effector T cells in vivo.

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Section: Discussionmentioning

confidence: 99%

Homeostatic regulation of CD8+ T cells by perforin

1999

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“…Despite this reservation, the notion we currently favor is that the K/D-restricted, effector T-cells for GVHD either do not require help or can produce their own endogenous help. On this point, it has recently been shown that certain K/D-restricted CTL can function in the absence of exogenous IL-2 (T-cell growth factor) {von , Widmer & Bach 1981, Raulet & Bevan 1982. Some of these cells produce IL-2-Iike factors.…”

Section: Discussionmentioning

confidence: 99%

Lethal GVHD Across Minor Histocompatibility Barriers: Nature of the Effector Cells and Role of the H‐2 Complex

Korngold

Sprent

1983

Immunological Reviews

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Transfer of T-cells to heavily irradiated, H-2-compatible mice frequently leads to a high incidence of lethal graft-versus-host disease (GVHD). Lymphoid cells depleted of Thy1+ cells fail to cause GVHD. Studies with a variety of different, H-2-compatible, strain-combinations suggest that minor, histocompatibility antigens (minor HA) are the main targets for eliciting lethal GVHD. Experiments in which T-cells are negatively selected to minor HA by acute blood-to-lymph recirculation through irradiated hosts have indicated that the T-cells eliciting GVHD to minor HA, are H-2-restricted. In H-2-compatible hosts, the donor T-cells recognize the minor HA of the host and become temporarily trapped in the lymphoid tissues for 1-2 days; during this stage of negative selection, the donor T-cells entering the lymph are specifically devoid of cells able to elicit GVHD against the host, minor HA on further transfer. When the selection host is H-2-different with respect to the donor T-cells, by contrast, the T-cells ignore the host, minor HA and negative selection fails to occur. The T-cells recirculate normally and are unimpaired in their capacity to elicit GVHD on further transfer. By the use of various H-2-recombinant mice as selection hosts it has been shown that, as for T-cells exerting cell-mediated lympholysis (CML) to minor HA in vitro, the T-cells which elicit lethal GVHD to minor HA comprise two distinct subsets of H-2-restricted cells. One subset recognizes minor HA in the context of H-2K (or K end) molecules whereas the other is specific for minor HA-plus-H-2D. Curiously, in marked contrast to the findings on CML responses in vitro, no evidence has been found that H-2I-restricted T-cells contribute to GVHD, either as effector cells or as helper cells. Purified populations of Lyt 1-2+ T-cells have potent GVHD activity, whereas Lyt 1+2- cells fail to cause GVHD. Studies with various types of bone-marrow chimeras suggest that in the induction phase, T-cells recognize minor HA only on lymphohematopoietic cells. In the effector phase, by contrast, non-marrow-derived cells appear to be the main targets of attack. Although the pathogenesis of GVHD is poorly understood, the lethal form of the disease probably reflects the penetration of mucosal surfaces by pathogenic organisms, perhaps as the result of direct destruction of epithelial cells by minor HA-specific cytotoxic lymphocytes. Direct support for this notion has yet to be obtained.

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“…In mice, both helper and cytotoxicT cells are involved in the rejection of allogeneic skin grafts (reviewed in [lo]). It has been demonstrated previously that third-party MHC disparities serve as inducer determinants, allowing the generation of sufficient help to activate CTL precursors (CTLp) [lo, 111, and that T cell help is required for the generation of CTL [12][13][14].…”

Section: Discussionmentioning

confidence: 99%

The mechanism of specific prolongation of class I‐mismatched skin grafts induced by retroviral gene therapy

et al. 1997

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In the present study, we examine the mechanism of specific hyporesponsiveness to major histocompatibility complex (MHC) class I-mismatched skin allografts induced by retrovirus-mediated gene transfer of an allogeneic class I gene into syngeneic bone marrow (BM). Using appropriate congenic recombinant mouse strains, we have mapped MHC determinants that are capable of restoring rapid rejection of Kb-bearing skin grafts. Our results indicate that either a single class I or a single class II alloantigen expressed on skin in association with Kb is able to restore the rapid rejection of Kb-mismatched skin grafts. These data suggest that third-party alloantigens expressed on skin in association with Kb abrogate hyporesponsiveness by providing T cell help. Consistent with this interpretation, spleen cells from mice reconstituted with Kb-transduced BM were unable to elicit a significant anti-Kb cytotoxic T lymphocyte response in vitro unless interleukin-2 was added to the culture medium. Skin graft survival was also analyzed on B10. AKM mice thymectomized 3-4 weeks post-reconstitution with Kb-transduced BM. Thymectomy did not result in significantly prolonged survival of B10. MBR skin grafts compared to euthymic controls, suggesting that even early after reconstitution, intrathymic deletion of Kb-reactive T cells must have been incomplete. Taken together, these data suggest that prolongation of skin allograft survival in this model is controlled at the level of T cell help.

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Helper T cells for cytotoxic T lymphocytes need not be I region restricted

Cited by 25 publications

References 45 publications

Homeostatic regulation of CD8+ T cells by perforin

Homeostatic regulation of CD8+ T cells by perforin

Lethal GVHD Across Minor Histocompatibility Barriers: Nature of the Effector Cells and Role of the H‐2 Complex

The mechanism of specific prolongation of class I‐mismatched skin grafts induced by retroviral gene therapy

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