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Interleukin-27 promotes CD8+ T cell reconstitution following antibody-mediated lymphoablation
Katayoun Ayasoufi, … , Robert L. Fairchild, Anna Valujskikh
Katayoun Ayasoufi, … , Robert L. Fairchild, Anna Valujskikh
Published April 4, 2019
Citation Information: JCI Insight. 2019;4(7):e125489. https://doi.org/10.1172/jci.insight.125489.
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Research Article Immunology Transplantation

Interleukin-27 promotes CD8+ T cell reconstitution following antibody-mediated lymphoablation

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Abstract

Antibody-mediated lymphoablation is used in solid organ and stem cell transplantation and autoimmunity. Using murine anti-thymocyte globulin (mATG) in a mouse model of heart transplantation, we previously reported that the homeostatic recovery of CD8+ T cells requires help from depletion-resistant memory CD4+ T cells delivered through CD40-expressing B cells. This study investigated the mechanisms by which B cells mediate CD8+ T cell proliferation in lymphopenic hosts. While CD8+ T cell recovery required MHC class I expression in the host, the reconstitution occurred independently of MHC class I, MHC class II, or CD80/CD86 expression on B cells. mATG lymphoablation upregulated the B cell expression of several cytokine genes, including IL-15 and IL-27, in a CD4-dependent manner. Neither treatment with anti-CD122 mAb nor the use of IL-15Rα–/– recipients altered CD8+ T cell recovery after mATG treatment, indicating that IL-15 may be dispensable for T cell proliferation in our model. Instead, IL-27 neutralization or the use of IL-27Rα–/– CD8+ T cells inhibited CD8+ T cell proliferation and altered the phenotype and cytokine profile of reconstituted CD8+ T cells. Our findings uncover what we believe is a novel role of IL-27 in lymphopenia-induced CD8+ T cell proliferation and suggest that targeting B cell–derived cytokines may increase the efficacy of lymphoablation and improve transplant outcomes.

Authors

Katayoun Ayasoufi, Daniel B. Zwick, Ran Fan, Suheyla Hasgur, Michael Nicosia, Victoria Gorbacheva, Karen S. Keslar, Booki Min, Robert L. Fairchild, Anna Valujskikh

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Figure 5

IL-15 signaling is not required for CD8+ T cell reconstitution after mATG treatment.

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IL-15 signaling is not required for CD8+ T cell reconstitution after mAT...
(A) C57BL/6J mice were transplanted with BALB/c heart allografts and treated with mATG alone (1 mg i.p. on days 0 and 4), with mATG plus anti-CD122 mAb (0.2 mg i.p. on days –1, 3, 6, 9, and 12), or mATG plus control rat IgG (0.2 mg i.p. on days –1, 3, 6, 9, and 12). The results are representative of 2 experiments with n = 4–5 mice/group/experiment; error bars represent SD. *P < 0.05, ns, P ≥ 0.05 for the comparison of mATG plus anti-CD122 and mATG plus rIgG groups by multiple t tests. (B) B6.WT and B6.IL-15Rα–/– mice were transplanted with BALB/c heart allografts and treated with mATG (1 mg i.p. on days 0 and 4). n = 4–5 mice per group, error bars represent SD. *P < 0.05, ***P < 0.001; ns, P ≥ 0.05 by multiple t tests.

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