The immunologic paradox of pregnancy has vexed the transplant community for >60 years. While Peter Medawar1 elegantly framed the question “How does this tolerance occur?” in 1953, it was the discovery of allospecific antibodies in the sera of parous women a few years later2 that provoked a related but much trickier question: how can the same immunizing event generate both tolerance and immunity? As the years passed and numerous investigators demonstrated that pregnancy induced not only T-cell dysfunction3-6 but the emergence of regulatory T cells,7,8 it seemed that every experiment only exacerbated the paradox instead of eliminating it. Nevertheless, transplant immunologists endeavor to this day to reconcile how immunologic tolerance of the fetus develops in parallel to the generation of allospecific antibodies.
The recent article by Suah et al9 from Anita Chong’s laboratory addresses this tolerance/sensitization paradox through the use of a murine model of pregnancy and transplantation. The authors used tetramers to identify B cells, CD8, and CD4 T cells within the maternal repertoire that were specific for transgenic antigens expressed by the fetus during pregnancy (“2 W-OVA”) after mating with 2 W-OVA.Balb/c male mice. In several experiments, postpartum female individuals received a heart or skin graft from a 2 W-OVA.F1 donor mouse. Transplant survival was monitored, and functionality of the fetal-specific T cells was assessed alongside fetal-specific B-cell and antibody (Ab) production. These parameters were similarly assessed in experiments where mice were treated with CD154 Ab + donor-specific transfusion (“CoB + DST”) or CTLA4Ig to induce long-term graft survival. Altogether, these experiments recapitulated the work of several prior groups, showing that after pregnancy (1) CD4+ regulatory T cells are expanded; (2) dysfunction develops in nonregulatory T cell CD4+ and CD8+ populations; and (3) allospecific Ab develops.2-7 Novel was the finding that postpartum animals resisted tolerance induction with CoB + DST or CTLA4Ig treatment. Subsequent experiments used Ab-deficient versus B cell–deficient mice to demonstrate that fetal-specific antibodies were necessary to resist tolerance induction by CoB. Another important finding was that postpartum animals lacking Ab and B cells could spontaneously accept fetus-matched heart transplants and that the addition of B cells without Ab secreting capacity was sufficient to break fetomaternal tolerance, promoting allograft rejection in these postpartum animals.
This work has several important implications. First, B cells alone and in the absence of Ab appear to be sufficient to override T-cell tolerance to the allograft induced by prior pregnancy. While it is unclear whether this occurs via antigen presentation in cognate B:T interactions or via B cell–mediated cytokine elaboration, the identification of B cells as a critical influencer of T-cell tolerance may allow the development of therapies specifically targeting these cells. Future studies which reveal the fate of allospecific B cells during pregnancy in addition to specific molecules expressed by B cells that influence T-cell function will be extremely important. Although these experiments suggest that allospecific B cells are generated outside the germinal center reaction during pregnancy, additional work in this area will be necessary to determine whether T follicular helper cells play any role in generating allospecific B-cell responses. Second, these experiments imply that allospecific T-cell function in parous mice can be tuned. Otherwise stated, allospecific T-cell dysfunction induced after pregnancy may be a reversible state that appears subject to environmental factors. This observation may help reconcile the disparate results of many studies of parous T cells over the years, as not all studies have found T-cell dysfunction to be particularly prominent.10-13 This observation also has implications for the molecular mechanisms governing allospecific T-cell dysfunction during pregnancy, suggesting that cytokine loci may be open and accessible for transcription but that these genes are somehow less responsive to signals downstream of the T-cell receptor.
Finally, this game-changing work from the Chong group showcases that the allospecific T- and B-cell responses induced during pregnancy are distinct and can be uncoupled from one another. Whereas the cytokine milieu in many pathogen responses appears to drive the concordant functionality of T and B cells, pregnancy appears to selectively promote allospecific T-cell tolerance while generating B cells and Ab that are competent to induce allograft rejection. Although these experiments provide limited mechanistic insight into how allospecific B cells become activated while T-cell functionality is compromised, we anticipate synthesis of these observations with our expanding knowledge about molecular mechanisms underlying T-cell dysfunction, and B-cell effector functionality will provide further insights and help translate these findings into meaningful clinical interventions.
In summary, the work of Suah et al9 has started the next chapter in our understanding of fetomaternal tolerance and the paradox of tolerance/sensitization. The identification of interacting cell types influencing transplant outcomes in sensitized patients is a critical step in our community’s ongoing pursuit to improve access, outcomes, and overall transplant quality of life.
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