Biological functions and molecular associations of the killer cell lectin-like receptor G1

The combination of innate and acquired immunity allows for precise immune reactions that result in containment and elimination of a variety of pathogens. The immune systems ability to discriminate between self and non-self is regulated by a balance between positive and negative signaling. The interaction between ligands and their receptors is critical to this recognition. The killer cell lectin-like receptor G1 (KLRG1) is a unique inhibitory receptor expressed on a phenotypically mature subset of resting NK cells as well as subsets of T cells in naive mice. In vivo, pathogenic immune system activation induces dramatic changes in the expression patterns of KLRG1 among the different cell subsets in both mice and humans. Work presented in this thesis is aimed to enhance our understanding of KLRG1 signaling properties and to clarify the functions of KLRG1 on immune cells. In Chapter II, we identify the broadly expressed adhesion molecules, N and E-cadherin as ligands for KLRG1. Additionally, we show that upon phosphorylation of the immunoreceptor tyrosine-based inhibitory motif (ITIM) tyrosine, KLRG1 recruits both SHIP-1 and SHP-2. We also delineate critical KLRG1 ITIM amino acid residues required for optimal association with the identified phosphatases and demonstrate that KLRG1 engagement can inhibit sub-optimal TCR signaling. Chapter III and VI identifies KLRG1 as a molecular marker that can be utilized for tracking NK cell recruitment into the immune response to MCMV infection. We provide evidence that NK cells undergo an accelerated maturation profile in response to MCMV, but their recruitment into the immune response is limited to the first three days of infection. We also show evidence that PD-1 may act as a molecular inhibitor for the maintenance of a naive population of NK cells capable of responding to additional stimulus. Additionally, we show that KLRG1 is differentially regulated in the salivary gland, where MCMV is permitted latency. Taken together, our results indicate that KLRG1 may differentially regulate NK cell and T cell functions through association with different ligands and recruitment of distinct phosphatases dependent on the microenvironment of the tissue involved.