Allograft Rejection Requires STAT5a/b-Regulated Antiapoptotic Activity in T Cells but Not B Cells

Abstract

STATs play key roles in immune function. We examined the role of STAT5a/b in allograft rejection. STAT5a/b-deficient mice showed a 4-fold increased survival time of heart allografts (p < 0.01). Unlike wild type, purified STAT5a/b−/− T cells transferred to Rag1−/− recipients failed to mediate heart allograft rejection until supplemented with STAT5a/b−/− B cells. In vitro, STAT5a/b−/− T cells did not proliferate in response to Con A or alloantigens but entered apoptosis within 48 h (95%). Activated STAT5a/b−/− T cells showed increased expression of proapoptotic (caspases, DNA repair genes, TNF/TNFR-associated factor family genes) and decreased antiapoptotic mRNAs in microarrays, while Western blots confirmed reduced antiapoptotic Bcl-2 and elevated proapoptotic Bax protein expression. Interestingly, at 24 h postactivation, STAT5a/b+/+ and STAT5a/b−/− T cells produced similar levels of IL-2, IL-4, IL-10, and IFN-γ mRNA; ELISPOT assay showed an equivalent number of IL-4- and IFN-γ-producing T cells in both STAT5a/b+/+ and STAT5a/b−/− splenic populations. Sera from STAT5a/b+/+ and STAT5a/b−/− rejectors had donor-specific IgM, IgG1, IgG2a, and IgG2b Ab, while STAT5a/b deficiency had no impact on B cell survival or proliferation in response to LPS. Compared with allografts from STAT5a/b+/+ recipients, heart allografts from STAT5a/b−/− recipients had markedly reduced infiltration by CD4 and CD8 T cells but increased infiltration by B cells and dense endothelial deposition of C4d, a marker of humoral rejection. Thus, activated STAT5a/b−/− T cells produce cytokines prior to entering apoptosis, thereby promoting differentiation of B cells yielding donor-specific IgM and IgG Ab that mediate allograft rejection.

Janus Tyrosine Kinases and Signal Transducers and Activators of Transcription Regulate Critical Functions of T Cells in Allograft Rejection and Transplantation Tolerance

“…Lack of IL-2-driven CD4 ϩ CD25 ϩ natural regulatory cells in Stat5a/b Ϫ/Ϫ mice disturbed homeostasis of self-tolerance leading to autoimmune diseases (75 ; Table 1A). Our recent results showed that Stat5a/b-deficient T cells failed to mediate allograft rejection (76), which coincided with apoptosis and elevated expression of multiple pro-apototic genes. Stat5a/b-deficiency had no impact on B cells and their in vivo production of alloantigen-specific IgM and IgG antibodies.…”

Interleukin-21 Is a Critical Regulator of CD4 and CD8 T Cell Survival during Priming under Interleukin-2 Deprivation Conditions

“…The cytokine signals leading to T cell activation and proliferation involve binding of common γ-chain (γc) cytokines (interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15 and IL-21) to their cognate receptors which in-turn activates Janus tyrosine kinases (Jak) 1 or Jak3 in the downstream milieu inducing transcription of multiple genes through signal transducers and activators of transcription (Stat)3, Stat6 and Stat5a/b pathways [1]. Among these cytokines, IL-2 is the major growth factor optimizing T cell responses as signaling through its high affinity IL-2 receptor (consisting of the α, β and common γ chains) and the Jak3-Stat5 axis is essential for the survival, proliferation and differentiation of antigen-activated T cells [2]–[5]. Naïve and memory T cells lack IL-2Rα (CD25) expression, but its expression is induced soon after antigen activation.…”

Regulation of T cell homeostasis by JAKs and STATs

“…Activated ∆NSTAT5a/b -/-T cells produced cytokines but failed to proliferate and instead entered apoptosis. Apoptosis of T cells correlated with increased expression of multiple proapototic genes (Bok, Blk, Bax, Bcl10, Nip3Myd88, Fadd), as revealed by microarray analysis [150]. Furthermore, only activated STAT5a/b--deficient T cells had decreased expression of antiapoptotic Bcl2 and induced proapoptotic Bak mRNA.…”