Veterinary Microbiology and Pathology

Junzo Norimine, DVM, PhD

Immunity is a key system that protects us from a variety of pathogens existing in our normal environment.  Without it, we are extremely vulnerable to infections.  Host immunity has to be functional to eliminate or at least control the growth of invading pathogens before they cause significant diseases.  It is therefore critical for all immunological defensive weapons to develop as fast as possible. While innate immunity provides early barriers to counter against infectious agents without previous exposure, adaptive immunity acts rapidly when exposed to the same pathogens previously encountered.  In order to establish protective immunity by vaccination, adaptive immunity, including humoral and cell-mediated immunity, has to be generated and ready for invading pathogens prior to infection.  Induction of immune responses, at the same time, must be tightly regulated so that excessive immune responses do not damage the host itself.  Evolutionarily, host immune defense has developed the system in which strong immune responses are elegantly regulated.  The helper T lymphocyte expressing CD4 molecules on the cell surface (CD4⁺ T cell, helper T cell) is such a critical regulator that orchestrates the highly complex immune system.

My research has focused on the role of CD4⁺ T cells in protective immunity against intraerythrocytic pathogens in cattle.  In addition to the well-known paradigm of Th1/Th2 CD4⁺ T cell subsets driving cell-mediated and humoral responses respectively, many other functionally distinct CD4+ T cell subsets have been discovered.  Numerous studies indicate that CD4⁺ T cell responses against infectious agents are extremely heterogeneous.  Immune regulation occurring in cattle infected by Anaplasma marginale, a tick-transmitted ehrlichial pathogen, gives us a unique opportunity to study immunoregulatory mechanisms involving persistent infection by intraerythrocytic pathogens.  The CD4⁺ T cells recognize antigenic epitopes only when presented by specific MHC class II molecules.  To characterize the highly heterogenous CD4⁺ T cell populations, we developed bovine MHC class II tetramers that are specific for a given antigen-specific CD4⁺ T cell and thus allow us to identify, enumerate, and characterize their functions.  Using the MHC class II tetramers, we found that antigen-specific memory/effector CD4⁺ T cells generated by immunizing with antigens derived from A. marginale were physically eliminated during infection.  This phenomenon, the clonal deletion of effector/memory CD4⁺ T cells, is thought to be closely associated with persistent infection established by A. marginale.  My long-term goal is to elucidate the mechanisms underlying persistent infection by investigating the regulatory role of antigen-specific memory/effector CD4⁺ T cells during acute and chronic infection.

Publications