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 7

AKT2 inhibits B55β expression.

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AKT2 inhibits B55β expression. (A–C) Ppp2r2b+/+ (WT) or Ppp2r2bfl/fl (cK...
(A–C) Ppp2r2b+/+ (WT) or Ppp2r2bfl/fl (cKO) T cells were activated and expanded in the presence of IL-2 for 10 days. (A) CD25 (IL-2Rα) expression on activated WT and cKO T cells. (B) STAT5 (Y694) phosphorylation in the presence of IL-2 (10 U/mL). A representative histogram and cumulative data from 2 independent experiments are shown. P = 0.46, unpaired t test. (C) STAT5 phosphorylation in WT and cKO mice upon IL-2 withdrawal. Data are expressed as mean ± SEM. Two independent experiments (n = 2 per group, per experiment). (D–G) Activated and expanded T cells were deprived of IL-2 (αIL-2) in the absence or presence of other cytokines, or were maintained in IL-2 while exposed to specific inhibitors. Live cells were quantified after 48 hours and compared with cells not deprived of IL-2 (IL-2). PPP2R2B mRNA levels were quantified 24 hours after IL-2 deprivation or after addition of inhibitors. (D) The effect of IL-7 (15 ng/mL) or IL-15 (20 ng/mL) was analyzed in cells deprived of IL-2. (E) Cells were incubated with tofacitinib (Tofa; 100 nM) or STAT5i (25 μM). (F) Cells were exposed to PD98039 (MEKi, 10 μM), SB202190 (p38i, 1 μM), or FR180204 (ERKi, 20 μM). (G) Cells were incubated with LY294002 (PI3Ki, 2 μM), MK-2206 (AKTi, 2 μM), or rapamycin (mTORi, 500 nM). Three independent experiments (n = 1–2 per experiment). Kruskal-Wallis test with Dunn’s multiple comparison analysis was used. *P < 0.05. (H) T cells were activated and infected with lentiviruses encoding shRNAs (scrambled, AKT1-, or AKT2-specific). PPP2R2B expression was quantified by qPCR. Four independent experiments (n = 1 per experiment). Friedman test with Dunn’s multiple comparison analysis was used. *P < 0.05.