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

Baratin, Myriam; Bonin, Karina; Chartier, Daniel

doi:10.1002/eji.200425309

Cited by 18 publications

(17 citation statements)

References 30 publications

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“…Indirect presentation has become increasingly appreciated as an important adjunct pathway in transplant allorecognition and in the case of skin grafts is sufficient to mediate rejection in the absence of direct presentation (5,7,(40)(41)(42)(43). Our results suggest that 2 additional mechanisms may therefore be important for insuring fetomaternal tolerance.…”

Section: Figurementioning

confidence: 69%

Constraints in antigen presentation severely restrict T cell recognition of the allogeneic fetus

Erlebacher¹,

Vencato²,

Price³

et al. 2007

J. Clin. Invest.

206

292

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How the fetus escapes rejection by the maternal immune system remains one of the major unsolved questions in transplantation immunology. Using a system to visualize both CD4 + and CD8 + T cell responses during pregnancy in mice, we find that maternal T cells become aware of the fetal allograft exclusively through "indirect" antigen presentation, meaning that T cell engagement requires the uptake and processing of fetal/placental antigen by maternal APCs. This reliance on a relatively minor allorecognition pathway removes a major threat to fetal survival, since it avoids engaging the large number of T cells that typically drive acute transplant rejection through their ability to directly interact with foreign MHC molecules. Furthermore, CD8 + T cells that indirectly recognize fetal/placental antigen undergo clonal deletion without priming for cytotoxic effector function and cannot induce antigen-specific fetal demise even when artificially activated. Antigen presentation commenced only at mid-gestation, in association with the endovascular invasion of placental trophoblasts and the hematogenous release of placental debris. Our results suggest that limited pathways of antigen presentation, in conjunction with tandem mechanisms of immune evasion, contribute to the unique immunological status of the fetus. The pronounced degree of T cell ignorance of the fetus also has implications for the pathophysiology of immune-mediated early pregnancy loss.

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Section: Figurementioning

confidence: 69%

Constraints in antigen presentation severely restrict T cell recognition of the allogeneic fetus

Erlebacher¹,

Vencato²,

Price³

et al. 2007

J. Clin. Invest.

206

292

View full text Add to dashboard Cite

show abstract

“…Recently, this route of activation of T cells reactive to alloantigen by the direct pathway has been called into question (29). Baratin et al (29) postulated that CD4 ϩ T cells that recognize alloantigen via the direct pathway were initially activated within the skin graft itself as they found little evidence of peripheral T cell priming.…”

Section: Discussionmentioning

confidence: 99%

“…Baratin et al (29) postulated that CD4 ϩ T cells that recognize alloantigen via the direct pathway were initially activated within the skin graft itself as they found little evidence of peripheral T cell priming. This result is in clear contrast to the data presented in this study.…”

Section: Discussionmentioning

confidence: 99%

Effector and Memory CD8+ T Cells Can Be Generated in Response to Alloantigen Independently of CD4+ T Cell Help

Jones

Carvalho-Gaspar

Luo

et al. 2006

The Journal of Immunology

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There is now considerable evidence suggesting that CD8+ T cells are able to generate effector but not functional memory T cells following pathogenic infections in the absence of CD4+ T cells. We show that following transplantation of allogeneic skin, in the absence of CD4+ T cells, CD8+ T cells become activated, proliferate, and expand exclusively in the draining lymph nodes and are able to infiltrate and reject skin allografts. CD44+CD8+ T cells isolated 100 days after transplantation rapidly produce IFN-γ following restimulation with alloantigen in vitro. In vivo CD44+CD8+ T cells rejected donor-type skin allografts more rapidly than naive CD8+ T cells demonstrating the ability of these putative memory T cells to mount an effective recall response in vivo. These data form the first direct demonstration that CD8+ T cells are able to generate memory as well as effector cells in response to alloantigen during rejection in the complete absence of CD4+ T cells. These data have important implications for the design of therapies to combat rejection and serve to reinforce the view that CD8+ T cell responses to allografts require manipulation in addition to CD4+ T cell responses to completely prevent the rejection of foreign organ transplants.

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“…Using a unique model of TCR Tg mice (2.102Tg mice), which allows us to study independently the two pathways of allorecognition during skin graft, we have previously shown that the same 2.102Tg alloreactive CD4 + T cells were able to initiate graft rejection by both pathways (19). In this model, the kinetics of rejection were similar, although the initiation of alloreactive responses seems to occur earlier in the direct pathway, suggesting that tolerance mechanisms were operational in this pathway.…”

Section: Resultsmentioning

confidence: 99%

Direct Alloreactivity Is More Susceptible to Regulation by Natural Regulatory T Cells Than Indirect Alloreactivity

Noel

Belghith

Bélanger

et al. 2013

The Journal of Immunology

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The contribution of natural CD4+CD25+ regulatory T cells (nTregs) in controlling graft rejection and the mechanism used remain controversial. Using the duality of the 2.102 TCR Ag recognition, we were able to study, for the first time to our knowledge, the involvement of nTregs in the two pathways of allorecognition in a murine adoptive transfer model in which TCR-transgenic nTregs were or were not depleted before transplantation. We show that nTregs used at a physiological ratio were able to delay graft rejection after direct alloreactivity by controlling proliferation and differentiation of alloreactive CD4+ conventional T cells in draining lymph nodes. In contrast, similar results were found in the indirect alloreactivity pathway only when nTregs were used in high numbers. In the latter pathway, nTregs used at a physiological ratio failed to delay graft rejection and to control proliferation of conventional T cells. These results support recent therapeutic approaches aimed at producing and using in vitro Ag-specific Foxp3+ nTregs to control graft rejection in transplantation. Finally, late inhibition of Th1 differentiation was shown in indirect alloreactivity, but this suppression could also be mediated by Foxp3+-induced Tregs.

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

Cited by 18 publications

References 30 publications

Constraints in antigen presentation severely restrict T cell recognition of the allogeneic fetus

Constraints in antigen presentation severely restrict T cell recognition of the allogeneic fetus

Effector and Memory CD8+ T Cells Can Be Generated in Response to Alloantigen Independently of CD4+ T Cell Help

Direct Alloreactivity Is More Susceptible to Regulation by Natural Regulatory T Cells Than Indirect Alloreactivity

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