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The Jenkins lab is focused on the basic biology of CD4+ T lymphocytes. These cells provide adaptive immunity to certain intracellular infections and tumors. This capacity is imbued by the T cell receptor (TCR). Each nascent CD4+ T cell produces a unique TCR by DNA recombination of gene segments during development in the thymus. A conserved part of each TCR confers a weak affinity for major histocompatibility complex II (MHCII) molecules, promiscuous peptide-binding receptors displayed on host antigen-presenting cells, while the variable parts confer an affinity for an MHCII-bound peptide of nine amino acids. To bind with a strong enough affinity to generate an activating signal, a TCR must interact with both the MHCII molecule and the peptide. Nascent CD4+ T cells that by chance generate TCRs with strong affinities for self p:MHCII complexes, receive an activating signal that causes apoptosis. Autoimmunity is thereby avoided. The CD4+ T cells that survive this process leave the thymus and are now called naïve cells. Naïve T cells circulate in a quiescent state through the secondary lymphoid organs of the host.
Following infection, B cells, macrophages, and dendritic cells take up microbes and cleave the associated proteins into peptides, some of which to bind to MHCII molecules. The newly formed MHCII-bound microbe peptides are displayed on the surface of the producing B cells, macrophages or dendritic cells. If a naïve CD4+ T cell with a TCR with a strong affinity for one of the microbe peptide:MHCII complexes encounters one of these cells, the T cell will proliferate and differentiate into effector cells that in turn enhance the microbe-killing functions of the cell that presented the MHCII-bound microbe peptide. Some of the effector cells become memory cells that survive long after the infection has been eliminated from the host.
One of our research interests relates to how the set of naïve CD4+ T cells in an individual is formed. To study this problem, we developed a peptide:MHCII tetramer and flow cytometry-based cell enrichment method to detect rare naïve CD4+ T cells specific for MHCII-bound foreign peptides. A foreign peptide is defined in this context as a peptide with an amino acid sequence different from any peptide in the host’s proteome. Using this method, we discovered that the number of naïve CD4+ T cells that recognize different MHCII-bound foreign peptides varies from peptide to peptide. We also found that larger naïve populations gave rise to larger immune responses. We now want to figure out why naïve cell T cell populations vary in size even before the host has been exposed to the peptide. Our main hypothesis is that MHCII-bound foreign peptides with small corresponding naïve cell populations are structurally homologous to a host peptide, which causes negative selection of some clones in the population.
We are studying costimulatory signals needed with TCR signals to produce maximal T cell activation. Our focus is on the best-known costimulatory receptor CD28, which binds to CD80 or CD86 on antigen-presenting cells. Despite the fact that CD28 is the target of antibody-based therapies for rheumatoid arthritis and transplant rejection, its signaling mechanism is still not understood. We are taking a retroviral transduction approach to determine how mutations in the CD28 cytoplasmic tail influence the generation of CD4+ effector T cells during infection. We hope to use this information to reveal the relevant signaling molecules that bind to CD28 when the TCR is also engaged. This approach could provide a starting point for the development of small molecules capable of blocking CD28 signaling.
We are also interested in the process that leads to immune memory by CD4+ T cells. This process begins during infection when naive CD4+ T cells expressing specific TCRs bind MHCII-bound microbial peptides and proliferate and differentiate into macrophage- or B cell-helping effector cells. It culminates when some of the effector cells become long-lived memory cells capable of rapid secondary responses. We are working on several fundamental questions related to this process. We are trying to understand how macrophage- and B cell-helping effector cells are generated simultaneously from a seemingly homogenous population of naïve cells. Additionally, we want to determine how CD4+ memory T cells emerge from a much larger population of effector cells. Both of these questions boil down to the issue of how effector cell heterogeneity is formed and propagated in the memory phase of the response. We have developed novel methods to track the fates of single CD4+ T cells at key branch points in the primary immune response to answer these questions. One of our main hypotheses is that the strength of the TCR signal received by a CD4+ T cell determines the type of effector cell that it will become. We are using similar methods to address related issues in B cell biology.
Recently, we become interested in the mechanisms whereby CD4+ T cells participate in protective immunity. CD4+ T cells are especially important for protecting hosts from microbes such as Salmonella enterica, which have evolved to live in the phagosomes of macrophages and dendritic cells. CD4+ T cells with TCRs specific for MHCII-bound microbe peptides control these phagosomal infections asymptomatically in most individuals by secreting cytokines that activate the microbicidal activities of infected phagocytes but in a way that inhibits the pathogen but does not eliminate it. Indeed, localized, controlled, persistent infection appears to be necessary to maintain large numbers of CD4+ effector T cells in a state of activation needed to eradicate systemic and more pathogenic forms of the infection. We are working to understand the mechanisms used by CD4+ T cells to limit intracellular infection, and by the microbes to resist eradication. We have developed a novel flow cytometry-based assay for detecting and characterizing Salmonella enterica-infected phagocytes and the microbes that they harbor. This approach is revealing unexpected complexity in the types of phagocytes that are infected and providing clues about how the infection is controlled but not eradicated. We hope that a deeper understanding of this process will hasten the advent of vaccines that currently do not exist for any phagosomal infection.