The physiological, cell-mediated immune response against pathogens and tumors, as well as the dysfunctional response during autoimmune reactions and graft rejections, involve many different types of molecules and mechanisms. Our long-term goal is to understand the contributions of the family class I Major Histocompatibility Complex antigens to these phenomena.
Much of what is known about the biology of class I MHC antigens was deduced from the studies of a few highly polymorphic "classical," or class la, MHC antigens. Whereas once considered evolutionarily conserved, now class Ia are regarded as variable between different species, having no direct orthologs between mice and man. These ubiquitously expressed transmembrane proteins carry out their critical functions in elimination of infected and malignantly transformed cells by presenting "nonself" peptides to Cytotoxic T Cells (CTL). They can also carry out opposing functions: by engaging activating or inhibitory receptors on Natural Killer (NK) cells class Ia molecules induce the killing or target cells or abort the killing program. The molecular, class I-mediated events that controlled the death vs. escape of the diseased cells are not well understood.
Even less is currently known about the numerous members of the heterogeneous family of the "non-classical," or class Ib, MHC and the effect that these oligo or monomorphic molecules have on activation or tolerance induction in the immune system.
One goal of our research is to understand the biology of Qa-2 class Ib MHC antigens. The Qa-2 locus is continuously reshaping itself by gene deletion/duplication suggesting that the levels of expression of the structurally invariant membrane and soluble Qa-2 are tightly controlled hosts from tumor growth. We now examine the mechanisms by which multiple isoforms of Qa-2 contribute to the rejection of malignant/dysregulated cells by CTL and NK and investigate the nature of the tumor/stress antigens that are presented by Qa-2 to the immune system.
Another aim of our research is to understand the role of class Ia and class Ib MHC pathways in the immunobiology of liver and gut, the two organs in which locally induced tolerance dominates over immune response to non-self antigens. The gastrointestinal tract and liver are of primary interest because in these sites the orally ingested harmless microflora as well as the disease-provoking pathogens come into a direct contact with the mammalian host. We identified several organ-specific class Ib products in these tissues and characterized the classical class I antigen assembly and presentation pathway in liver. We now investigate how liver and gut-specific class Ib MHC molecules regulate the functions of the immune cells populating these tissues and how they influence tolerance/immune response in the local environment.
Our experiments employ molecular, biochemical, biophysical, cellular, and transgenic approaches.
Gao, J-X, Liu, X., Wen, J., Caligiuri, M.A., Stroynowski, I., Zheng P., Liu, Y. (2004) Two-signal requirement for activation and effector function of natural killer cell response to allogeneic tumor cells. Blood 102, 4456-4463.
Chiang, E.Y., Henson, M. and Stroynowski, I. (2003) Correction of defects responsible for impaired Qa-2 class Ib MHC expression on melanoma cells protects mice from tumor growth. J.Immunol. 170, 4515-4523.
Chiang, E.Y., Henson, M. and Stroynowski, I. (2002) Tumor cells expressing the nonclassical Major Histocompatibility Complex molecule Qa-2 are are protected from Natural Killer cell-and Lymphokine-Activated Killer cell mediated cytolysis. J.Immunol. 168, 2200-2211.
He, X., Tabaczewski, P., Ho, J., Stroynowski, I. and K.C. Garcia. (2001) Promiscuous antigen presentation by the non-classical MHC Ib Qa-2 is enabled by a shallow, hydrophobic groove and self-stabilized peptide conformation. Structure 9, 1213-1224.
Zappacosta, F., Tabaczewski, P., Parker, K.C., Coligan, J.E., and Stroynowski, I. (2000) The murine liver- specific nonclassical MHC molecule Q10 binds a classical peptide repertoire. J. Immunol. , 164, 1906-1915.