Protein phosphatase 2A B55β limits CD8+ T cell lifespan following cytokine withdrawal
Noé Rodríguez-Rodríguez, Iris K. Madera-Salcedo, J. Alejandro Cisneros-Segura, H. Benjamín García-González, Sokratis A. Apostolidis, Abril Saint-Martin, Marcela Esquivel-Velázquez, Tran Nguyen, Dámaris P. Romero-Rodríguez, George C. Tsokos, Jorge Alcocer-Varela, Florencia Rosetti, José C. Crispín
Noé Rodríguez-Rodríguez, Iris K. Madera-Salcedo, J. Alejandro Cisneros-Segura, H. Benjamín García-González, Sokratis A. Apostolidis, Abril Saint-Martin, Marcela Esquivel-Velázquez, Tran Nguyen, Dámaris P. Romero-Rodríguez, George C. Tsokos, Jorge Alcocer-Varela, Florencia Rosetti, José C. Crispín
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Research Article Autoimmunity

Protein phosphatase 2A B55β limits CD8+ T cell lifespan following cytokine withdrawal

Abstract

How T cells integrate environmental cues into signals that limit the magnitude and length of immune responses is poorly understood. Here, we provide data that demonstrate that B55β, a regulatory subunit of protein phosphatase 2A, represents a molecular link between cytokine concentration and apoptosis in activated CD8+ T cells. Through the modulation of AKT, B55β induced the expression of the proapoptotic molecule Hrk in response to cytokine withdrawal. Accordingly, B55β and Hrk were both required for in vivo and in vitro contraction of activated CD8+ lymphocytes. We show that this process plays a role during clonal contraction, establishment of immune memory, and preservation of peripheral tolerance. This regulatory pathway may represent an unexplored opportunity to end unwanted immune responses or to promote immune memory.

Authors

Noé Rodríguez-Rodríguez, Iris K. Madera-Salcedo, J. Alejandro Cisneros-Segura, H. Benjamín García-González, Sokratis A. Apostolidis, Abril Saint-Martin, Marcela Esquivel-Velázquez, Tran Nguyen, Dámaris P. Romero-Rodríguez, George C. Tsokos, Jorge Alcocer-Varela, Florencia Rosetti, José C. Crispín

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Figure 8

B55β controls the pathogenic capacity of CD8+ T cells.

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B55β controls the pathogenic capacity of CD8+ T cells. (A–F) OT-I cells ...
(A–F) OT-I cells differentiated into CTLs. After 4 days, they were i.v. injected into RIP-mOVA or WT mice. Blood glucose was quantified every day. (A) Pancreatic inflammation was scored: 0, no inflammation; 1, small perivascular infiltrates; 2, inflammatory infiltrates surrounding the islets; 3, inflammatory infiltration and/or destruction of the islets. Cumulative data of 2 independent experiments (n = 4–6 mice per group) are shown. Unpaired t test, **P ≤ 0.01. (B) Representative images of H&E-stained pancreata from A are shown. Arrowheads indicate inflammatory infiltrates. Scale bars: 100 μm. (C) Glucose levels in RIP-mOVA mice that received WT or cKO OT-I CTL, or PBS. Cumulative data from 2 independent experiments are shown. (D) Incidence of diabetes in RIP-mOVA mice (n = 4–6 mice per group). Log-rank (Mantel-Cox) test, **P ≤ 0.01. (E) Transferred cells (CD45+CD8+Vα2+Vβ5+CD44+) in draining lymph nodes and pancreata of recipient RIP-mOVA mice 5 days after CTL transfer. Cumulative data of 2 experiments (n = 3–5 mice per group). Unpaired t test, *P ≤ 0.05. (F) Dead donor cells (GhostDye+) in the spleens of recipient mice after CTL transfer. Cumulative data from 2 experiments (n = 3–5 mice per group). Unpaired t test, *P ≤ 0.05. (G–K) A quantity of 106 OT-I CD45.2 Ppp2r2b+/+ or Ppp2r2bfl/fl were adoptively transferred into CD45.1 mice. The next day, 104 CFU of LM-OVA were i.v. injected into the recipient mice. After 30 days, 2 × 105 B16-OVA melanoma cell line cells were implanted in the left flanks of the animals (G). Survival (H) and tumor growth (I–J) were monitored. (K) Tumor weight on day 21. Cumulative data from 2 experiments (n = 3–5 mice per group). One-way (H) and 2-way (J) ANOVA and unpaired t test (K) were used. Mean ± SEM is depicted. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001.