Michael S Kuhns

Michael S Kuhns

Associate Professor, Immunobiology
Associate Professor, Genetics - GIDP
Associate Professor, BIO5 Institute
Primary Department
Department Affiliations
Contact
(520) 626-6461

Work Summary

Michael Kuhns' research program is focused on (i) increasing our basic understanding of how T cell fate decisions are made (e.g. development, activation, differentiation, effector functions), and (ii) increasing their working knowledge of how to manipulate these decisions to direct T cells towards a desired outcome, such as increasing responses to vaccines or tumors, preventing transplant rejection, or attenuating autoimmunity.

Research Interest

What we’re interested in: For all vertebrates, from mice to humans, vaccine-induced and naturally primed immunity to pathogens require that coordinated, multi-cellular responses emerge from a myriad of ‘conversations’ that take place between cells of the immune system. These conversations occur via cytokines and chemokines that are secreted by one cell and detected via receptors on other cells. They also occur via direct contacts between membrane-bound molecules at the interface between two cells. Ultimately, these conversations are responsible for insuring that an appropriate immune response occurs in the appropriate place, and at the appropriate time, to fight an infection without inducing an inappropriate response to commensal organisms or self-antigens. The molecules on T cells that are involved in these conversations include but are not limited to: the T cell receptor (TCR), which provides clonotypic antigen specificity to T cells; the CD3δε, γε, and ζζ signaling dimers that connect the TCR to the intracellular signaling machinery; the CD8 and CD4 coreceptors that provide major histocompatibility molecule (MHC)-restriction for T cells that recognize antigenic peptides bound to class I or II MHC, respectively; and costimulatory molecules, such as CD28, that provide information about the activation state of an antigen presenting cell (APC) and thus the context in which an antigen occurs. We are interested in understanding how the individual contributions from this chorus of molecules are integrated to achieve the critical balance between tolerance of self-antigens and protective immunity against pathogenic infection. Specifically, we are working to understand how the information that is critical for T cells to decide if and how they should respond to antigen is conveyed from an antigen presenting cell (APC) to a T cell. We are using a variety of classic molecular, cellular, and biochemical techniques, as well as more modern live cell imaging approaches, to probe the molecular mechanisms involved in these processes. We are also developing mouse model systems to determine how individual mechanisms contribute to T cell responses in vivo during pathogenic infection or autoimmunity. Altogether, our work is aimed at increasing our basic and practical appreciation of T cell responses and regulation.

Publications

Kuhns, M. S., & Badgandi, H. B. (2012). Piecing together the family portrait of TCR-CD3 complexes. Immunological reviews, 250(1), 120-43.

The pre-T-cell receptor (TCR)-, αβTCR-, and γδTCR-CD3 complexes are members of a family of modular biosensors that are responsible for driving T-cell development, activation, and effector functions. They inform essential checkpoint decisions by relaying key information from their ligand-binding modules (TCRs) to their signaling modules (CD3γε + CD3δε and CD3ζζ) and on to the intracellular signaling apparatus. Their actions shape the T-cell repertoire, as well as T-cell-mediated immunity; yet, the mechanisms that underlie their activity remain an enigma. As with any molecular machine, understanding how they function depends upon understanding how their parts fit and work together. In the 30 years since the initial biochemical and genetic characterizations of the αβTCR, the structure and function of the individual components of these family members have been extensively characterized. Cumulatively, this information has allowed us to piece together a portrait of the αβTCR-CD3 complex and outline the form of the remaining family members. Here we review the known structural and functional characteristics of the components of these TCR-CD3 complex family members. We then discuss how these data have informed our understanding of the architecture of the αβTCR-CD3 complex as well as their implications for the other family members. The intent is to provide a framework for considering: (i) how these thematically similar complexes diverge to execute their specific functions and (ii) how our knowledge of the form and function of these distinct family members can cross-inform our understanding of the other family members.

Zeng, X., Wei, Y., Huang, J., Newell, E. W., Yu, H., Kidd, B. A., Kuhns, M. S., Waters, R. W., Davis, M. M., Weaver, C. T., & Chien, Y. (2012). γδ T cells recognize a microbial encoded B cell antigen to initiate a rapid antigen-specific interleukin-17 response. Immunity, 37(3), 524-34.

γδ T cells contribute uniquely to immune competence. Nevertheless, how they function remains an enigma. It is unclear what most γδ T cells recognize, what is required for them to mount an immune response, and how the γδ T cell response is integrated into host immune defense. Here, we report that a noted B cell antigen, the algae protein phycoerythrin (PE), is a murine and human γδ T cell antigen. Employing this specificity, we demonstrated that antigen recognition activated naive γδ T cells to make interleukin-17 and respond to cytokine signals that perpetuate the response. High frequencies of antigen-specific γδ T cells in naive animals and their ability to mount effector response without extensive clonal expansion allow γδ T cells to initiate a swift, substantial response. These results underscore the adaptability of lymphocyte antigen receptors and suggest an antigen-driven rapid response in protective immunity prior to the maturation of classical adaptive immunity.

Kuhns, M. S., Davis, M. M., & Garcia, K. C. (2006). Deconstructing the form and function of the TCR/CD3 complex. Immunity, 24(2), 133-9.

When T cells encounter antigens via the T cell antigen receptor (TCR), information about the quantity and quality of antigen engagement is relayed to the intracellular signal transduction machinery. This process is poorly understood. The TCR itself lacks a significant intracellular domain. Instead, it is associated with CD3 molecules that contain intracellular signaling domains that couple the TCR/CD3 complex to the downstream signaling machinery. The earliest events in TCR signaling must involve the transfer of information from the antigen binding TCR subunit to the CD3 signaling subunits of the TCR/CD3 complex. Elucidating the structural organization of the TCR with the associated CD3 signaling molecules is necessary for understanding the mechanism by which TCR engagement is coupled to activation. Here, we review the current state of our understanding of the structure and organization of the TCR/CD3 complex.

Kuhns, M. S., & Davis, M. M. (2008). The safety on the TCR trigger. Cell, 135(4), 594-6.

In this issue, Xu et al. (2008) provide evidence for a new mechanism of T cell receptor regulation. Prior to activation, basic residues in the cytoplasmic domain of the signaling subunits of the T cell receptor associate with the plasma membrane such that the key signaling tyrosines are sequestered in the bilayer.

Lee, M. S., Glassman, C. R., Deshpande, N. R., Badgandi, H. B., Parrish, H. L., Uttamapinant, C., Stawski, P. S., Ting, A. Y., & Kuhns, M. S. (2015). A Mechanical Switch Couples T Cell Receptor Triggering to the Cytoplasmic Juxtamembrane Regions of CD3ζζ. Immunity, 43(2), 227-39.

The eight-subunit T cell receptor (TCR)-CD3 complex is the primary determinant for T cell fate decisions. Yet how it relays ligand-specific information across the cell membrane for conversion to chemical signals remains unresolved. We hypothesized that TCR engagement triggers a change in the spatial relationship between the associated CD3ζζ subunits at the junction where they emerge from the membrane into the cytoplasm. Using three in situ proximity assays based on ID-PRIME, FRET, and EPOR activity, we determined that the cytosolic juxtamembrane regions of the CD3ζζ subunits are spread apart upon assembly into the TCR-CD3 complex. TCR engagement then triggered their apposition. This mechanical switch resides upstream of the CD3ζζ intracellular motifs that initiate chemical signaling, as well as the polybasic stretches that regulate signal potentiation. These findings provide a framework from which to examine triggering events for activating immune receptors and other complex molecular machines.