Category: Autoimmune rheumatologic diseases
Activated T cell apoptosis represents an essential mechanism of peripheral tolerance. Defects in this process cause autoimmunity and cancer. Here, we demonstrate the role of PP2A B55β as a key regulator of T cell lifespan, essential for immune homeostasis.
T cell-specific deficiency of B55β caused an accumulation of activated/memory CD8 T cells in aging mice. Following an infection with Listeria monocytogenes, B55β-deficient CD8 T cells exhibited significantly higher survival than their WT counterparts. The accumulating cells expressed an activated/memory phenotype and produced high levels of IFN-γ. The failure to remove activated T cells was due to defective apoptosis. Proteomic analyses revealed that, during cytokine withdrawal, WT T cells inactivate AKT. This leads to the activation of FoxO factors which promote the transcription of Hrk. In B55β-deficient T cells, AKT remains active and Hrk is not upregulated. The importance of this pathway was demonstrated by the fact that Hrk silencing conferred resistance to apoptosis in in vitro and in vivo systems. To evaluate the importance of B55β as a regulator of CD8 T cell survival, we transferred B55β-deficient or sufficient OT-I cells into RIP-mOVA mice. 80% of the mice that received KO cells developed dense islet infiltrates and diabetes (vs. 20% of the controls). On the other hand, transferred KO cells controlled the growth of an OVA-expressing melanoma significantly better than WT cells.
These results identify B55β as an essential regulator of cellular lifespan and demonstrate the mechanism through which it controls apoptosis.
Noé Rodríguez-Rodríguez– Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
J. Alejandro Cisneros-Segura– Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
George Tsokos– Professor, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School
Jorge Alcocer-Varela– Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
Florencia Rosetti– Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
Jose Crispin– Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran