Adrian C. Hayday
Immune Responses and Autoimmune Disorders
Our laboratory is interested in the molecular processes involved in the development of immune responses and immunological diseases. To accomplish our goals we combine a variety of approaches. The major read-out is the response of mice to a reproducible, natural system of infection, the major input is lines of novel mutant mice that we and others develop by use of homologous recombination in embryonic stem (es) cells, followed by blastocyst injection and transfer to term in pseudopregnant foster mothers. This is generally termed "knockout technology."
As an example of how these approaches are combined, we are studying the functions of gamma delta ([gamma]d) T cells, a distinct subset of T cells that bear on their surfaces, antigen binding T cell receptors (TCRs) comprising [gamma]d subunits, distinct from the a[beta] TCRs borne by the major T cell subset of the body. [gamma]d T cells are conserved in all vertebrates, but currently are of unknown function. Interestingly, we have recently shown that after infection of mice with Eimeria, a naturally-occurring parasite of the gut, [gamma]d T cells reduce the pathology without affecting the virulence of the pathogen. Consistent with this, recent data indicate that [gamma]d [Tau] cells also reduce the effect of a[beta] T cells in causing autoimmune disease Furthermore, our laboratory is increas-ingly embracing studies that indicate a bona fide capacity of T cells to reduce tumor progression. All these studies should help us elucidate the mechanisms by which [gamma]d T cells provide great benefits to the host.
Infections with Eimeria are probably typical of many human-pathogen inter-actions in the g.i. tract, including those with HIV. The deficiency in a[beta] T cells induced by HIV is well known, and is to some extent modeled by knockout mice lacking a[beta] T cells. We showed last year that such mice develop normally, but go on to display substantial antibody production, directed not against microbes, but primarily against self. Those autoreactive responses are a candidate model for autoimmunity that characterizes late-stage AIDS patients, and other persons, such as transplant patients, suffering from immunodeficiency. Currently we are particularly interested in whether this type of general immunodeficiency also holds clues to the development of organ-specific autoimmune diseases such as type I diabetes.
Complementing these studies, scientists in our group are directly examining T cell development, particularly the interplay of differentiation and cell cycle control. Currently our data define an interesting G1 cell cycle block in which cells sit while their antigen receptor genes are rearranged.