Targeting Janus tyrosine kinase 3 (JAK3) with an inhibitor induces secretion of TGF-β by CD4+ T cells

Abstract

Regulatory T cells (Tregs) are critical for the peripheral maintenance of the autoreactive T cells in autoimmune disorders such as type 1 diabetes (T1D). Pharmacological inhibition of Janus tyrosine kinase 3 (JAK3) has been proposed as a basis for new treatment modalities against autoimmunity and allogeneic responses. Targeting JAK3 with an inhibitor has previously been shown to exhibit protective action against the development of T1D in non-obese diabetic (NOD) mice. As the mechanism of such preventative action has been unknown, we hypothesized that JAK3 inhibition induces generation of Tregs. Here, we show that the JAK3 inhibitor 4-(49-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P131) suppresses proliferation of short-term cultured NOD CD41 T cells through induction of apoptosis, while promoting survival of a particular population of long-term cultured cells. It was found that the surviving cells were not of the CD4 1 CD25 1 FoxP3 1 phenotype. They secreted decreased amounts of IL-10, IL-4 and interferon (IFN)-c compared to the cells not exposed to the optimal concentrations of JAK3 inhibitor. However, an elevated transforming growth factor (TGF)-b secretion was detected in their supernatants. In vivo treatment of prediabetic NOD mice with WHI-P131 did not affect the frequency and number of splenic and pancreatic lymph node CD4 1 FoxP3 1 Tregs, while generating an elevated numbers of CD4 1 FoxP3 2 TGF-b-secreting T cells. In conclusion, our data suggest an induction of TGF-b-secreting CD4 1 T cells as the underlying mechanism for antidiabetogenic effects obtained by the treatment with a JAK3 inhibitor. To our knowledge, this is the first report of the JAK3 inhibitor activity in the context of the murine Tregs.

Chicken-Specific Kinome Array Reveals that Salmonella enterica Serovar Enteritidis Modulates Host Immune Signaling Pathways in the Cecum to Establish a Persistence Infection

“…JAK3 is the only JAK family member involved in all phases of T cell biology: development, proliferation, and differentiation [ 76 , 77 , 78 ]. For T cell differentiation, JAK3, along with IL-4, steer Th2 cell differentiation [ 78 ], but inhibition of JAK3 generates the induction of Tregs [ 79 , 80 ]. Therefore, the dephosphorylation of JAK2 and JAK3 found in the present studies would result in a change in the functional immune phenotype of the cecal environment that benefits the establishment of a tolerant mucosal immune response against the bacterial colonization.…”

Exposure to DDT metabolitep,p′-DDE increases autoimmune type 1 diabetes incidence in NOD mouse model

“…Additional studies involving measures of TGF should be performed to further characterize DDE effects on T reg cells. The protective role of T reg cells in the pathogenesis of T1D has been well documented (Cetkovic-Cvrlje et al, 2012;Riley et al, 2009). In addition, decreased levels of protective anti-diabetogenic cytokines have been linked with acceleration of diabetes development and increased incidence.…”

“…For years, besides cytotoxic T-cells, the T-helper (T H )1/T H 2 paradigm, while over-simplified, has provided a conceptual scaffold for understanding immunopathogenesis of T1D: T H 1 response, with its cytokines interleukin (IL)-2 and interferon (IFN)-, has been considered pathogenic, in contrast to protective T H 2 response, mediated by IL-4 and IL-10 (Muller et al, 2002;Rabinovitch, 1998). More recently, the regulatory IL-10 and transforming growth factor (TGF)--secreting T-regulatory (T reg ) cells have been recognized by their regulatory influence and considered protective (Cetkovic-Cvrlje et al, 2012;Riley et al, 2009), whereas T H 17 cells, characterized by secretion of IL-17, have been recognized as harmful in development of T1D (Bettelli et al, 2007). The NOD mouse model, with its spontaneous development of T-cell-mediated and T-cell-dependent T1D, has been accepted as the best experimental model for studying immunopathogenesis of this disease and the effects of different compounds in the context of T1D protection/aggravation (Shoda et al, 2005).…”

Exposure to polychlorinated biphenyl-153 decreases incidence of autoimmune Type 1 diabetes in non-obese diabetic mice

“…T H 1 responses, with cytokines interleukin (IL)-2 and interferon (IFN)-c, have been considered pathogenic, in contrast to protective T H 2 responses mediated by IL-4 and IL-10 (Cetkovic-Cvrlje et al 2003;Sia 2005). More recently, regulatory T (T reg )-cells have been recognized as protective, whereas IL-17-secreting T H 17 cells have been considered as harmful in the development of T1D (Cetkovic-Cvrlje et al 2012). The non-obese diabetic (NOD) mouse model, with its spontaneous development of T-cell-mediated T1D, has been accepted as the best experimental model for studying immunopathogenesis of this disease and the effects of different compounds in the context of T1D protection/ aggravation (Shoda et al 2005).…”

“…Several subsets of T-cells, characterized by different immunophenotypes and cytokine profiles, have been implied as major players in the immunopathogenesis of T1D (Shoda et al 2005;Cetkovic-Cvrlje et al 2012). For years, besides cytotoxic T-cells, the T helper (T H )1/T H 2 paradigm -while oversimplified -has provided a conceptual scaffold for understanding the immunopathogenesis of T1D.…”