Tumor progression locus 2 inhibits regulatory T cell development and immunosuppressive functions (LYM8P.640)

• Published in: The Journal of immunology (1950) 2015-05, Vol.194 (1_Supplement), p.201-201.16
• Main Authors: Li, Xin, Acuff, Nicole, Peeks, Angela, Kirkland, Rebecca, Hardwick, Kara, Nagy, Tamas, Watford, Wendy
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.194.Supp.201.16

Regulatory T cells (Tregs) are a specialized subset of immunosuppressive T cells that function to maintain peripheral tolerance. We previously demonstrated that the serine-threonine kinase, tumor progression locus 2 (Tpl2, also designated Cot/Map3k8), regulates TCR signaling and inflammatory cytokine secretion in CD4+ T cells. Herein, we demonstrate that Tpl2 is preferentially expressed by Tregs and regulates their development and functions. Tpl2-/- mice exhibited increased proportions of thymic natural Tregs (nTregs) as well as peripheral splenic Tregs, in vivo. Enhanced Treg development was due to a T cell autonomous defect, since Treg development from tpl2-/- naïve T cells cultured in vitro was similarly enhanced, and peripheral Treg proportions were also increased within the tpl2-/- donor compartment of mixed bone marrow chimeras. This defect depended upon TCR signal strength and was enhanced at low antigen concentrations. Importantly, tpl2-/- Tregs had increased expression of the immunosupressive cytokines, IL-10 and IL-35, and provided better protection than wild-type Tregs in vivo in a T cell transfer model of colitis. These results demonstrate that Tpl2 has an important physiological role in limiting Foxp3 expression, Treg development and functions. Therefore, Tpl2 inhibition could potentially be used to deviate pathological immune responses in a variety of autoimmune diseases towards a protective, tolerogenic response through preferential Treg induction.