Casey T. Weaver, MD
The Weaver Lab is interested in the development of function of CD4 T cells with emphasis on mechanisms by which CD4 T cells control adaptive immunity in host defense and how these cells become dysregulated in immune-mediated disease of the intestines and development of colorectal cancer. Major on-going efforts include studies of intestinal Th17 and eTreg cell development and function, regulation of mucosal immunity by nuclear receptors, mechanisms controlling late-onset sepsis in neonates, mechanisms controlling Tfh—non Tfh development effector cell fate decisions, immune mechanisms of homeostatic and pathologic responses of intestinal lymphocytes to the enteric microbiota, and the interplay of immune cells and the transformed intestinal epithelium in colorectal cancer.
Nuclear Receptor Control of T Cell Function in Discrete Intestinal Microenvironments. The gut is a central immunological organ, where host-microbe interactions shape immune tolerance and inflammation, both locally and systemically. Yet prevailing immunological views conflate the two distinct organs that comprise the gut—small and large intestine (or SI and LI)—which impedes more robust understanding of mucosal immune regulation, and misses opportunities to develop safer, more targeted therapies for human inflammatory bowel diseases (IBDs). The premise of this application, founded on recent discoveries from, and synergy between, the two PIs (Sundrud, Weaver), is that mucosal CD4+ T cells use distinct sets of nuclear receptors (NRs) in the SI and LI to interface with divergent classes of host- and microbe-derived metabolites, respectively. Recent work from the Sundrud lab establishes that Foxp3– T effector (Teff) subsets—Th1, Th17 cells—use a NR with no previously known immunological function, the constitutive androstane receptor (CAR/Nr1i3), to direct a 'hepatocyte-like' transcriptional response to contend with potentially cytotoxic bile acid (BA) concentrations in the SI. A large gradient of BAs exists between the SI (millimolar) and LI (micromolar) due to 'enterohepatic' circulation—primary BAs synthesized in the liver, stored in the gallbladder, and secreted post-prandially into the duodenum are actively reabsorbed by specialized enterocytes in the ileum for portal recirculation to the liver. Because BAs are lipophilic, they can be toxic and pro-inflammatory in enterohepatic tissues; a host of nuclear receptors—including CAR—have evolved to suppress BA toxicity in hepatocytes and enterocytes. Our data suggest that enterohepatic circulation creates a uniquely harsh SI microenvironment to which infiltrating T cells must adapt to maintain tolerance and tissue homeostasis. The LI, by contrast, harbors 103-107 times more bacteria than the SI, and ~1000-fold less BAs. Accordingly, microbes and their metabolites—short chain fatty acids (SCFAs; e.g., butyrate), secondary BAs (produced via microbial metabolism of residual primary BAs)—become central to immune regulation in the LI. SCFAs inhibit histone deacetylase enzymes (HDACs) and stabilize Foxp3 gene expression in peripherally-induced T regulatory cells (iTregs), whereas secondary BAs promote LI Treg maintenance through another NR, vitamin D receptor (VDR). Thus, while antigens from the enteric flora are required for priming both pro- and anti-inflammatory T cell responses throughout the intestinal tract, we hypothesize that marked differences in the abundance of bugs and bile in the SI vs. LI establish consequential metabolite gradients that are sensed by different NRs to instruct compartmentalized T cell regulatory functions. We test this hypothesis through complementary, but not inter-dependent, Aims, leveraging new mouse models, as well as a library of recombinant protein-based NR activity assays, to define the mechanisms governing the transcriptional regulation, biochemical activation, and downstream cellular functions of CAR (in SI Teff cells) and VDR (in LI iTreg cells). Successful completion of these Aims will establish new biological paradigms and inform more precise approaches to treat human IBDs.
Current Grant Support
|R01 DK169864||Weaver (PI)||04/01/2022 – 03/31/2027|
Coordination of Innate and Adaptive Immune Cells in Intestinal Barrier Defense
This project is defining the specialized role to T cells in host protection of the intestinal mucosa against enteropathogenic bacteria.
|R01 AI163063||Sundrud, Weaver (MPls)*||09/23/2021 – 08/31/2026|
Nuclear Receptor Control of T Cell Function in Discrete Intestinal Microenvironments
This project will define mechanisms through which mucosal CD4 T cells employ discrete sets of nuclear receptors to regulate immune homeostasis in the unique microenvironments of the small and large intestine.
|R01 AI164712||Weaver, Gray (MPIs)*||08/01/2021 – 07/31/2026|
Targeting the Intestinal Mucosa and Microbiome to Prevent Neonatal Late-onset Sepsis
This is a Dual-PI project (with Dr. Michael Gray, UAB) that is elucidating host and microbiome factors that predispose to neonatal dysbiosis that leads to neonatal late-onset sepsis.
|U01 AI163063||Sundrud, Weaver, Pipkin (MPls)*||07/30/2021 – 04/30/2026|
Nuclear Receptor Networks in Mucosal Immune Regulation
This goal of project is to define mechanisms by which nuclear receptors contribute to transcriptional networks that control T cell regulatory functions in the small and large intestines.
|UAB Internal||Weaver (PI)||04/01/2021 – 03/31/2023|
UAB O'Neal Comprehensive Cancer Center
Deciphering the Role of IL-22 in Colitis-Associated Colorectal Cancer
The goal of this grant is to understand the contributions of IL-22 produced from innate or adaptive immune cells in promoting or restraining the development of colorectal cancer.
|R01 DK115172||Weaver, Hatton (MPls)*||09/17/2017 – 08/31/2022|
Mechanisms Controlling Regulatory T Cell Effector Function in IBD
This project is defining the regulation of the II10 gene locus by a transcriptional repressor in the content of effector Treg cell function.
Casey T. Weaver, MD
Pham, D., D.J. Silberger, M. Gao, K.N. Nguyen, R.D. Hatton+, and C.T Weaver+. Batf stabilizes the Th17 cell developmental program through impairment of Stat5-dependent recruitment of Ets1-Runx1 complexes. EMBO J (in revision).
Zindl, C.L., S.J. Witte, V.A. Laufer, M. Gao, Z. Yue, Daniel J. Silberger, S.N. Harbour, J.R. Singer, Duy Pham, C.E. Moseley, B. Cai, H. Turner, F.E. Lund, B.A. Vallance, A.F. Rosenberg, J.Y. Chen, R.T. Hatton1 and C.T. Weaver. A non-redundant role for T cell-derived IL-22 in antibacterial defense of colonic crypts. Immunity 55:494-511, 2022.
Kahan. S.M., R.K. Bakshi, J.T. Ingram, R.C. Hendrickson, E.J. Lefkowitz, D.K. Crossman, L.E. Harrington, C.T. Weaver, and A.J. Zajac. Intrinsic IL-2 production by effector CD8 T cells affects IL-2 signaling and promotes fate decisions, stemness, and protection. Science Immunology 7:eabl6322, 2022.
Chen, M.L., X. Huang, H. Wang, C. Hegner, Y. Liu, J. Shang, A. Eliason, H. Diao, H. Park, B. Frey, G. Wang, S.A. Mosure, L.A. Solt, D.J. Kojetin, A. Rodriguez-Palacios, D.A. Schady, C.T. Weaver, M.E. Pipkin, D.D. Moore, and M.S. Sundrud. CAR directs T cell adaptation to bile acids in the small intestine. Nature 593:147-151, 2021.
Glover ME, Cohen JL, Singer JR, Sabbagh MN, Rainville JR, Hyland MT, Morrow CD, C.T. Weaver, Hodes GE, Kerman IA, and SM Clinton. Examining the role of microbiota in emotional behavior: antibiotic treatment exacerbates anxiety in high-anxiety-prone male rats. Neuroscience, 459:179-197, 2021.
Moldoveanu Z., H. Suzuki, C. Reily, K. Satake, L. Novak, N. Xu, Z.Q. Huang, B. Knoppova, A. Khan, S. Hall, H. Yanagawa, R. Brown, C.J. Winstead, D.B. O'Quinn, A. Weinmann, A.G. Gharavi, K. Kiryluk, B.A. Julian, C.T. Weaver, Y. Suzuki, and J. Novak. Experimental evidence of pathogenic role of IgG autoantibodies in IgA nephropathy. J. Autoimmun. 118:102593, 2021.
C.T. Weaver. One road to the TH17 pathway: How TH1 led to TH17 (and vice versa), and first became last. Nature Immunology 21:819-821, 2020.
Camacho, V., V.R. Matkins, S.B. Patel, J.M.Lever, Z. Yang, L. Ying, A.E. Landuyt, E.C. Dean, J.F. George, H. Yan, P.B. Ferrell, C.L. Maynard, C.T. Weaver, H.R. Turnquist, and R.S. Welner. Bone marrow Tregs mediate stromal cell function and support hematopoiesis via IL-10. J. Clin. Invest. Insight 5:e135681, 2020.
Harbour, S.N., D.F. DiToro, S.J. Witte, C.L. Zindl, T.R. Schoeb, G.W. Jones, S.A. Jones, R.D. Hatton, and C.T. Weaver. Th17 cells require ongoing classical IL-6 receptor signaling to retain transcriptional and functional identity. Science Immunology 5:eeaw2262, 2020.
DiToro, D.F., S.N. Harbour, Steven Witte, Vincent Laufer, M. Gao, C.E. Moseley1, H. Turner, J. Bruning, C.H. Conover,, R.D. Hatton, S.J. Frank5, and C.T. Weaver. Insulin-like growth factors are key regulators of Th17-Treg cell balance in autoimmunity. Immunity 52:650-667, 2020.
Evonuk, K.S., R.E. Doyle, C.E. Moseley, I.M. Thornell, K. Adler, A.M. Bingaman, M.O. Bevensee, B. Min, C.T. Weaver, and T.M. DeSilva. Reduction of AMPA receptor activity on mature oligodendrocytes attenuates loss of myelinated axons in autoimmune neuroinflammatyion. Sci Adv 6:eaax5936, 2020.