Adaptor proteins play a crucial role in receptor signaling. Even though they lack enzymatic activity, these proteins have modular domains that are able to interact with other proteins and form signaling complexes, leading to the activation or inhibition of signaling cascades. Src-like adapter proteins (SLAP and SLAP2) constitute a family of proteins that are expressed in a variety of cell types but are studied most extensively in lymphocytes. To date, no in vivo function in T lymphocytes has been ascribed to SLAP2. We have identified SLAP2 as an essential molecule controlling the development and function of a population of innate T lymphocytes, the Invariant Natural Killer T (iNKT) cells. While numerically low, these iNKT cells are immunologically important and have been implicated in regulating a multitude of immune responses associated with a broad range of diseases, including autoimmunity and allergy but also infectious diseases, cancer and metabolism. We propose to characterize the phenotypic, functional and molecular consequences of SLAP2-deficiency in iNKT cells. Not only will the proposed experiments provide a more comprehensive understanding of iNKT cell development and function, but this research will help identify ways to skew the development of one subset of iNKT cells over another and effectively treat diseases caused and/or modulated by iNKT cells. In order to harness the immunotherapeutic potential of these innate T cells, it is important to gain a full appreciation of their function and development
Invariant Natural Killer T (iNKT) cells are a type of immune cell that is numerally small but immunologically important to our health. Numerous studies in humans and mice have suggested that if you do not have a normal population of iNKT cells, you have an increased susceptibility to autoimmune diseases and cancers. The proposed studies aim at examining how the adaptor molecule SLAP2 controls iNKT cell subset development. These studies will open up substantial new possibilities for understanding iNKT cell development and effector programming so that it can be exploited for therapeutic usage to improve human health.
| Tuttle, Kathryn D; Krovi, S Harsha; Zhang, Jingjing et al. (2018) TCR signal strength controls thymic differentiation of iNKT cell subsets. Nat Commun 9:2650 |
| Sundararaj, Srinivasan; Zhang, Jingjing; Krovi, S Harsha et al. (2018) Differing roles of CD1d2 and CD1d1 proteins in type I natural killer T cell development and function. Proc Natl Acad Sci U S A 115:E1204-E1213 |
