Sandra M Hayes, PhD
- Assistant Professor of Microbiology and Immunology
Research Programs and Affiliations
- Biomedical Sciences Program
- Microbiology and Immunology
- Research Pillars
Education & Fellowships
- PhD: University of Connecticut Health Center, 1991, Biomedical Sciences
- BA: Franklin and Marshall College, 1986, Biology
Roles of B lymphoid kinase (Blk) in lymphocyte development and activation as well as in preventing autoimmunity
Signaling through the T cell antigen receptor (TCR) is required at many stages in the life of a T cell; it is required during development in the thymus for lineage commitment and repertoire selection and in the periphery for homeostasis and for effector and memory T cell differentiation. The TCR complex is organized into two functional domains: an antigen-binding clonotypic heterodimer and a signal transducing complex composed of invariant CD3γ, -δ, -ε, and TCRζ chains. In all jawed vertebrates, there are two different clonotypic heterodimers (TCRαβ and TCRγδ), which define the αβ and γδ T cell lineages, respectively. αβ- and γδTCRs also differ in the subunit composition of their signal transducing complexes, in that αβTCRs contain both CD3γε and CD3δε dimers, whereas γδTCRs contain only CD3γε dimers. Remarkably, stimulation of the γδTCR is not impaired despite the absence of CD3δ. In fact, comparison of the signaling potential of the two TCRs demonstrates that the γδTCR transduces signals better than the intact αβTCR in assays that measure calcium mobilization, ERK activation and cellular proliferation. Collectively, these observations reveal a fundamental difference in the primary structure and signaling potential of αβ- and γδTCR complexes. This discovery has a great impact on our perception of γδ T cells.
A major research interest of our lab is to understand why signal transduction by the γδTCR is more robust than that of the αβTCR. We hypothesized that the observed signaling differences are due to differences in the intracellular signaling pathways coupled to the αβ- and γδTCRs. To test this hypothesis, we employed global gene expression profiling to identify signaling molecules that are differentially expressed between mature αβ and γδ T cell populations. Using this strategy, we found that B lymphoid kinase (Blk), a B cell-specific Src family kinase that is a key component of the B cell antigen receptor (BCR) signaling pathway, is expressed in γδ T cells but not in αβ T cells. Subsequent protein expression studies showed that Blk is expressed only in a small subset of mature γδ T cells, indicating that Blk cannot be responsible for the enhanced signaling ability of the γδTCR per se. To determine the biological significance of Blk expression in γδ lineage cells, we analyzed γδ T cell development and function in Blk−/− mice and found that Blk is required for the development and differentiation of IL-17–producing γδ T (γδ-17) cells, an effector subset that is an important mediator in multiple infectious and autoimmune diseases. Combining our findings with those of other groups who also study γδ-17 cells, we have developed a three-stage model for their development and differentiation. Our current studies are designed to test and build upon this model.
In light of our recent discovery that Blk expression is not limited to B cells, we performed a more comprehensive analysis of Blk expression patterns in hematopoietic cells with the goal of identifying other lineages that express Blk. During this analysis, while using B cell subsets as positive staining controls, we found that Blk is differentially expressed between the two mature splenic B cell populations, marginal zone (MZ) and follicular B cells. Specifically, MZ B cells expressed approximately twice as much Blk as FO B cells. Further analysis of Blk expression in B lineage cells from bone marrow and spleen demonstrated that its expression is dynamic throughout development, and that its differential expression between MZ and FO B cells is due to its upregulation in MZ B cells and its downregulation in FO B cells. In addition, we found that the upregulation of Blk is crucial for the development and activation of MZ B cells, as mice with reduced levels, or a loss, of Blk generate MZ B cells that are fewer in number but exhibit augmented in vitro and in vivo responses to BCR stimulation compared to WT mice. Notably, with age, this B cell hyper-responsiveness led to autoantibody production. Thus, our study has revealed a previously unappreciated role for Blk not only in the development and activation of MZ B cells but also in the control of B cell tolerance. To understand how high levels of Blk regulate MZ B cell development and function, we are currently identifying which signaling pathways upregulate Blk expression during MZ B cell development and which require Blk activity during MZ B cell development and activation.
The completion of both the Human Genome Project and the International HapMap Project has allowed researchers to scan markers across the human genome to identify genes that contribute to complex human diseases. This strategy, which is known as genome-wide association analysis, was recently used to discover new susceptibility loci for systemic lupus erythematosus (SLE), a multisystem autoimmune disorder that afflicts more than 1.5 million Americans. One of these new genetic loci is a promoter region allele that results in a reduction (i.e., 25% to 50% decrease depending on whether individuals are heterozygous or homozygous for the allele) in BLK gene expression. To capitalize on this finding, we developed an experimental mouse model system, in which Blk expression levels are reduced to levels comparable to those in individuals homozygous for the risk allele. We are currently using this mouse model to understand how reducing Blk expression levels confers susceptibility to SLE.
Hayes, S.M. and Love, P.E. 2002. Distinct structure and signaling potential of the γδTCR complex. Immunity 16:827-838.
Hayes, S.M., Laky, K., El-Khoury, D., Kappes D.J., Fowlkes B.J. and P.E. Love. 2002. Activation-induced modification in the CD3 complex of the γδ T cell receptor. J. Exp. Med. 196:1355-1361.
Hayes, S.M., Shores, E.W. and P.E. Love. 2003. An architectural perspective on signaling by the pre-, αβ and γδ T cell receptors. Immunol. Rev. 191:28-37.
Hayes, S.M., Li, L.Q. and P.E. Love. TCR signal strength influences αβ/γδ lineage fate. 2005. Immunity 22:582-593. •Recommended by Faculty of 1000
Hayes, S.M. and P.E. Love. Stoichiometry of the murine γδ T cell receptor. 2006. J. Exp. Med. 203:47-52.
Hayes, S.M. and P.E. Love. Strength of signal: A fundamental mechanism for cell fate specification. 2006. Immunol. Rev. 209:170-175.
Hayes, S.M. and P.E. Love. A retrospective on the requirements for γδ T cell development. 2007. Immunol. Rev. 215:8-14.
Laird, R.M.* and S.M. Hayes. 2009. Profiling of the early transcriptional response of murine γδ T cells following TCR stimulation. Mol. Immunol. 46:2429-2438.
Laird, R.M.* and S.M. Hayes. 2009. Dynamics of CD3γε and CD3δε dimer expression during murine T cell development. Mol. Immunol. 47:582-589.
Laird, R.M.* and S.M. Hayes. 2010. Roles of the Src tyrosine kinases Lck and Fyn in regulating γδTCR signal strength. PLoS ONE 5:e8899.
Hayes, S.M., R.M. Laird* and P.E. Love. 2010. Beyond αβ/γδ lineage commitment: TCR signal strength regulates γδ T cell maturation and effector fate. Semin. Immunol. 22:247-251.
Laird, R.M.,* K. Laky and S.M. Hayes. 2010. Unexpected role for the B cell-specific Src family kinase B lymphoid kinase in the development of IL-17-producing γδ T cells. J. Immunol. 185:6518-6527.
Samuelson, E.M.,* R.M. Laird,* A.C. Maue, R. Rochford and S.M. Hayes. 2011. Blk haploinsufficiency impairs the development, but enhances the functional responses, of MZ B cells. Immunol. Cell Biol. Doi:10.1038/icb.2011.76.
Hayes, S.M. and R.M. Laird.* 2012. Genetic requirements for the development and differentiation of interleukin-17-producing γδ T cells. Crit. Rev. Immunol. 32:81-95.
Eric Wohlford received a 2012 travel award from the American Society of Tropical Medicine and Hygiene and spent two months in Kenya working in the lab of Rosemary Rochford, PhD, professor and chair of Upstate’s Department of Microbiology & Immunology. Eric studied the effects of malaria on B cells (producers of antibodies that fight infection) and Epstein-Barr Virus infection in the region. “Tropical medicine is unique, in that small, focused improvements in patient care make dramatic improvements in the well-being of patients,” he said.