T cells reactive to a single immunodominant self-restricted allopeptide induce skin graft rejection in mice.

Valujskikh, Anna; Matešić, Damir; Gilliam, Anita C.; Anthony, Donald D.; Haqqi, Tariq M.; Heeger, Peter S.

doi:10.1172/jci893

Cited by 88 publications

(51 citation statements)

References 28 publications

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“…Moreover it allows comparison of each alloreactive pathway in a context where precursor frequency and repertoire are similar. In that context, our results confirmed previous studies that demonstrated that indirect recognition of a single immunodominant epitope can by itself initiate graft rejection [15,16]. However, they contrast with other studies showing that activation of alloreactive T cells in DLN or spleen follows similar kinetics [17,18].…”

Section: Discussionsupporting

confidence: 90%

Frontline: Peripheral priming of alloreactive T cells by the direct pathway of allorecognition

2004

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Recent studies, though controversial, have suggested that secondary lymphoid organs may not constitute an essential site for the initiation of immune responses to transplant antigens. However, this issue has never been examined in the context of direct and indirect allorecognition. Here, we characterized immune responses arising in draining lymph nodes and skin allografts, in a murine model based on a single T cell clonotype where these two pathways can be independently studied. In this model, graft rejection by the direct or the indirect pathway occurred with similar kinetics, although initiation of the alloreactive responses was clearly different. During indirect responses, expansion and activation of alloreactive T cells were first observed in draining lymph nodes, at day 7 post-transplant, and graft-infiltrating T cells were observed later, at day 11. In striking contrast, directly activated alloreactive T cells were detected at an early stage inside the graft, and only later in the draining lymph nodes, after skin allograft rejection was almost completed. These results suggest that sensitization of naive T cells through the direct pathway could take place outside secondary lymphoid organs. See accompanying Commentary: http://dx

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Section: Discussionsupporting

confidence: 90%

Frontline: Peripheral priming of alloreactive T cells by the direct pathway of allorecognition

2004

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“…It is noteworthy that in this model, anti-donor cytolytic activity mediated by CD8 ϩ T cells was thought to be the effector mechanism (22,23). Other lines of evidence have been provided suggesting that in the absence of a direct pathway, an indirect alloresponse is sufficient to ensure rejection of allografts (5,24). Valujskikh et al (24) have reported that reconstitution of SCID mice with a CD4…”

Section: R Ecognition By Recipient T Lymphocytes Of Alloantigens Exprmentioning

confidence: 94%

“…Other lines of evidence have been provided suggesting that in the absence of a direct pathway, an indirect alloresponse is sufficient to ensure rejection of allografts (5,24). Valujskikh et al (24) have reported that reconstitution of SCID mice with a CD4…”

Section: R Ecognition By Recipient T Lymphocytes Of Alloantigens Exprmentioning

confidence: 99%

Role of CD4+ and CD8+ T Cells in Allorecognition: Lessons from Corneal Transplantation

Boisgerault

Liu

Anosova

et al. 2001

The Journal of Immunology

110

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Corneal transplantation represents an interesting model to investigate the contribution of direct vs indirect Ag recognition pathways to the alloresponse. Corneal allografts are naturally devoid of MHC class II+ APCs. In addition, minor Ag-mismatched corneal grafts are more readily rejected than their MHC-mismatched counterparts. Accordingly, it has been hypothesized that these transplants do not trigger direct T cell alloresponse, but that donor Ags are presented by host APCs, i.e., in an indirect fashion. Here, we have determined the Ag specificity, frequency, and phenotype of T cells activated through direct and indirect pathways in BALB/c mice transplanted orthotopically with fully allogeneic C57BL/6 corneas. In this combination, only 60% of the corneas are rejected, while the remainder enjoy indefinite graft survival. In rejecting mice the T cell response was mediated by two T cell subsets: 1) CD4+ T cells that recognize alloantigens exclusively through indirect pathway and secrete IL-2, and 2) IFN-γ-producing CD8+ T cells recognizing donor MHC in a direct fashion. Surprisingly, CD8+ T cells activated directly were not required for graft rejection. In nonrejecting mice, no T cell responses were detected. Strikingly, peripheral sensitization to allogeneic MHC molecules in these mice induced acute rejection of corneal grafts. We conclude that only CD4+ T cells activated via indirect allorecognition have the ability to reject allogeneic corneal grafts. Although alloreactive CD8+ T cells are activated via the direct pathway, they are not fully competent and cannot contribute to the rejection unless they receive an additional signal provided by professional APCs in the periphery.

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“…The main obstacle resides in the difficulty of finding situations where indirect sensitization represents the only pathway available for activation of alloreactive T cells. The most convincing approaches that have been tried to date involve either the transplantation of MHC class II molecule-deficient organs or the adoptive transfer of in vitro-derived T cells sensitized by indirect recognition of allopeptides (6,13). Although elegantly designed, these experiments have major weaknesses.…”

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confidence: 99%

Acute Rejection in the Absence of Cognate Recognition of Allograft by T Cells

Braun¹,

Grandjean

Feunou³

et al. 2001

The Journal of Immunology

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We studied the effects of the indirect pathway of allograft recognition using T cells from TCR transgenic Marilyn mice, which recognize the male Ag H-Y in an I-Ab-restricted fashion. The T cells are not alloreactive to the H-2k haplotype, because they are not activated when adoptively transferred into recombinase-activating gene-2−/− common γ-chain−/− double-mutant H-2k male or female mice. However, skin from H-2k males, but not from H-2k females, is acutely rejected by recombinase-activating gene-2−/− transgenic female recipients. In vitro, Marylin spleen cells primed by H-2k skin grafting proliferated and secreted both IL-4 and IFN-γ in response to H-2k male stimulators. However, the removal of H-2b APC from the responding population abolished the response. Taken together, these results show that the indirect recognition that triggers rejection in this model is due to the recognition of H-Y Ag shed from H-2k male allograft and presented by the recipient’s own I-Ab APC to transgenic T cells. This study demonstrates unequivocally the capacity of naive CD4+ T cells to promote the rejection of allografts through mechanisms that involve indirect destruction of grafted tissues.

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T cells reactive to a single immunodominant self-restricted allopeptide induce skin graft rejection in mice.

Cited by 88 publications

References 28 publications

Frontline: Peripheral priming of alloreactive T cells by the direct pathway of allorecognition

Frontline: Peripheral priming of alloreactive T cells by the direct pathway of allorecognition

Role of CD4+ and CD8+ T Cells in Allorecognition: Lessons from Corneal Transplantation

Acute Rejection in the Absence of Cognate Recognition of Allograft by T Cells

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