Specific recognition of antigen by T cells is critical to host-immune response. Alteration in the repertoire of antigens recognized has implications in the areas of autoimmunity and host microbial defense. T cells expressing the gamma-delta T cell antigen receptor gamma delta (gd) TCR represent a distinct subset. Yet, little is known about the role of gd T cells in human disease and the antigens that they recognize. In man, there exist two sub-population, of cells expressing gd TCRs encoded for by Vdelta1 or Vdelta2 gene segments. The Vdelta+ population, predominant in the circulation, responds to non-peptied alkyl pyrophosphate antigens present in a number of microorganisms and may function in defense against infection. Vdelta1+gdT cells predominate in the tissues yet their antigenic, specificity and potential role in human disease remain to be defined. It has previously been demonstrated that CD1 cell surface molecules can present lipid antigens to T cells expressing the alpha beta TCR. Preliminary studies by the candidate have demonstrated that Vdelta1+gd T cells can recognize lipid antigens presented by CD1c. The candidate will further define the basic biology of gd T cells and test the following hypotheses: (1) CD1 restricted recognition of lipid antigens represents a major reactivity of the Vdelta1+gd T cell population. (2) Gd T cell recognition of CD1 restricted self lipids exist in the autoimmue disease systemic lupus erthematosus (SLE) and contributes to immune modulation of the disease. (3) Vdelta1+gd T cells recognize CD1 restricted exogenous microbial lipid antigens and may play a role in host defense. The candidate will now generate additional gd T cell clones reactive against CD1 restricted lipid antigens from normal individuals and patients with SLE.
In Aim 1, CD1 restriction, cell surface phenotype and TCR usage will be determined.
Aim 2 will study the functional characteristics of CD1 reactive gd T cells in normal individuals and patients with SLE including cytokine production, mechanism of cytolysis and in the case of SLE, ability to influence autologous autoantibody production Aim 3 will determine if the precusor frequency of gd T cells reactive agianis CD1 restricted self-lipids is increased in SLE compared to normal individuals. The candidate has had extensive, but informal, training in immunology. He seeks additional intensive, and formal mentored training to provide the necessary intellectual and technical tools to achieve independence as a scientist. As a pediatric rheumatologist, his long-term goal is to study the role of T cells in the inflammatory disease of children.
|Leslie, David S; Dascher, Christopher C; Cembrola, Katherine et al. (2008) Serum lipids regulate dendritic cell CD1 expression and function. Immunology 125:289-301|
|Vincent, Michael S; Leslie, David S; Gumperz, Jenny E et al. (2002) CD1-dependent dendritic cell instruction. Nat Immunol 3:1163-8|
|Leslie, David S; Vincent, Michael S; Spada, Franca M et al. (2002) CD1-mediated gamma/delta T cell maturation of dendritic cells. J Exp Med 196:1575-84|