Constraints in antigen presentation severely restrict T cell recognition of the allogeneic fetus
Adrian Erlebacher, … , Dorothy Zhang, Laurie H. Glimcher
Adrian Erlebacher, … , Dorothy Zhang, Laurie H. Glimcher
Published May 1, 2007
Citation Information: J Clin Invest. 2007;117(5):1399-1411. https://doi.org/10.1172/JCI28214.
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Research Article Immunology

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

Abstract

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.

Authors

Adrian Erlebacher, Daniela Vencato, Kelly A. Price, Dorothy Zhang, Laurie H. Glimcher

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Figure 8

Defective OVA-specific cytotoxic responses in Act-mOVA–mated mice.

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Defective OVA-specific cytotoxic responses in Act-mOVA–mated mice. In vi...
In vivo cytotoxicity assays were performed by injecting 50:50 mixtures of CFSEhi SIINFEKL-pulsed B6CBAF1 splenocytes (target cells) and CFSElo unpulsed splenocytes (control cells). The ratio (r) was calculated as the number of CFSEhi to CFSElo cells remaining 16 hours later; low ratios imply high levels of SIINFEKL-specific killing. (A) Low levels of SIINFEKL-specific cytotoxicity in Act-mOVA–mated mice receiving OT-I cells. E10.5–E11.5 pregnant or virgin females injected with OT-I cells were treated as indicated, then assayed 6 days later. Data are representative of 2 independent experiments, encompassing n = 4 Act-mOVA–mated mice. (B) Absent SIINFEKL-specific cytotoxicity in Act-mOVA–mated mice with unmanipulated T cell repertoires, unless treated with anti-CD40 antibodies and poly(I:C). E10.5–E13.5 pregnant or virgin females were treated as indicated, then assayed 6 days later. Data are from of 1 of 6 independent experiments. Each histogram shows representative data for a treatment group, except in the case of Act-mOVA–mated females treated with anti-CD40 antibodies and poly(I:C), for which results for the mouse with the highest cytotoxicity are shown. The total number of mice in each group over all experiments is indicated. (C) CTL responses in Act-mOVA–mated females treated with CD40 antibodies and poly(I:C). The percentage of induced SIINFEKL-specific killing was calculated by normalizing the CFSEhi to CFSElo ratio for individual anti-CD40/poly(I:C)-treated mice to the mean value of this ratio for their respective nonadjuvant-treated group. Act-mOVA–mated mice were assayed in 3 independent experiments; the number of Act-mOVA concepti/total concepti for each of these mice is shown.