Michael Brehm's Laboratory
My laboratory’s research focus is to understand the immune mechanisms that regulate human T cell responses. We are investigating human T cell biology in 3 distinct areas; 1) the role of positive and negative costimulatory signals in controlling antigen-specific T cell responses, 2) the ability of CD4+/FOXP3+ Treg to suppress antigen-specific T cells responses and 3) defining the thymic developmental stages for human autoreactive T cells.
T cell activation.
T cells are a component of the adaptive immune system and are integral to the control of intracellular pathogens, the rejection of transplanted non-self (allogeneic) tissues, and to the development of autoimmune diseases such as type 1 diabetes and multiple sclerosis. The classical response of naïve T cells to antigenic stimulation is initiated by engagement of the T cell receptor (TCR) with peptide-MHC complexes, which stimulates a programmed pathway of differentiation that is tightly coupled to cell division (Figure 1). Naïve T cells that receive appropriate signals will differentiate into effector T cell populations with functional capacity, including cytokine secretion and cytotoxic activity. Following clearance of antigen load, the effector T cell population undergoes a contraction phase with a small proportion of T cells surviving into a memory population. Upon reencountering the same or similar antigen, the memory T cell compartment will mount a rapid recall response and in instances of infection, will provide an enhanced level of protection as compared to the naïve immune system.
T cells require 3 distinct signals for optimal activation (Figure 2) that include TCR engagement (signal 1), costimulation (signal 2) and cytokines (signal 3). The quality and strength of these 3 signals will determine the functionality and magnitude of effector response and the ability of the memory population to respond to secondary challenge. Much of our current understanding of T cell activation and function is based on experiments done in small animal rodent models, specifically mice. While these animal studies have laid the foundation for our understanding of T cell immunity and T cell dysfunction, there are many inherent differences between human and murine T cell biology.