​Immunology, Cancer and Metabolism Research areas- Rincon’s Group

1. Role of p38 MAPK and GSK3β in T cell development and function. We were the first to show that p38 MAPK plays an important role in early thymocyte development. p38 MAPK is classically defined as a signaling pathway induced by cell stress that promotes cell death. In contrast, we showed that p38 MAPK could provide survival signals to thymocyes in vivo, a major paradigm shifting. While searching for the mechanism by which p38 MAPK could promote survival, we were the first to identify GSK3β as a novel target of p38 MAPK, uncovering a novel mechanism for the regulation of GSK3β through Ser389 (mouse)/Thr390 (human) (Thornton et al. Science 2008). The major discoveries that these studies have revealed are: 1) p38 MAPK selectively accumulates in the nucleus in response to DNA DSB, 2) phosphorylation of GSK3β on Ser389 by p38 MAPK is induced specifically by DSB and is restricted to the nucleus, and 3) inactivation of GSK3β through Ser389 phosphorylation is a mechanism to promote survival in response to DSB generated by TCRβ VDJ recombination (Thornton et al. Nat. Communication 2016). These findings represent a major breakthrough in understanding the developmental mechanism generating TCR diversity. We are currently investigating how survival while undergoing DNA repair during TCRβ chain early in thymocyte development can determine the presence or absence of specific TCR and how this could
   impact the immune response to infections and autoimmune diseases. 
   
2. IL-6 as a key regulator of T cell immune response in inflammatory diseases and cancer. The other visionary area of research that our group has been working on for over two decades is the role of IL-6 in CD4 T cell differentiation and effector function. We showed that IL-6 regulates Th2 and Th1 differentiation using different signaling pathways (Diehl et al Immunity 2000; Diehl et al. J. Exp. Med. 2002). Later she showed the pivotal role of IL-6 on IL-21 production by CD4 T cells, and the regulation of antibody production on B cells indirectly by IL-21 in vitro and in vivo during influenza virus immunization, representing a shift from the dogma at that time (Dienz et al. J. Exp. Med. 2009). Another recent challenge of the dogma was the revelation that CD8 cells can act as helper of B cells by secreting IL-21 when activated in the presence of IL-6 and IL-21 promotes Ab production (Yang et al. J. Exp. Med. 2016). Regarding contributions to the asthma field, Dr. Rincon’s studies using mouse models have shown for the first time that IL-6 contributes to mucosal hyperplasia in allergic airway inflammation in part by promoting the production of IL-13 by CD4 cells, and these studies go from mouse to asthmatic patients (Neveu et al. J. Immunol. 2009; Neveu et al. Respir. Res. 2010; Neveu et al. AJRCMB, 2011). We are currently working on IL-6 role in COPD patients. We have identified a novel mechanism by which IL-6 regulates CD4 effector function: through its effect on mitochondrial membrane potential and mitochondrial Ca++ (Yang et al.  eLife, 2015). In addition, Dr. Rincon has been working on IL-6 in breast cancer since late 90s. We were the first showing that IL-6 promotes chemoresistance in breast cancer  cells (Conze et al. Cancer Research 2001), and more recently we have shown that IL-6 contributes to metastases induced by the acute inflammatory response in mammary tumors triggered by a core biopsy (Hobson et al. 2013).  These studies were further followed up in breast cancer patients showing that biopsy in patients trigger an eosinophilic immune response and it is associated with an increased proliferation of the tumor cells surrounding the biopsy wound (Szalayova et al. Breast Cancer Res. Treat. 2016). We are now following these studies further.
   
3. Metabolism in cancer chemoresistance. Through the studies in the area of chemoresistance in breast cancer, we have identified MCJ/DnaJC15 as a regulator of multidrug resistance. We were the first to show that the MCJ/DnaJC15 cochaperone is silenced in chemoresistant breast cancer cell lines and that MCJ regulates chemotherapy response in these cells (Hatle, 2007 Mol. Cell. Biol.). Our more recent studies (Fernandez-Cabezudo et al. JCI-Insight, 2016) show that low MCJ levels in breast tumor is prognosis marker for poor response to chemotherapy in breast cancer patients and that eliminating MCJ causes multidrug resistant in vivo in a mouse model of mammary tumor. We have shown that MCJ is a negative regulator of Complex I, the first endogenous negative regulator of Complex I described (Hatle et al. MCB. 2013). We are investigating how mitochondrial metabolism contributes to cancer chemoresistance and how
   we can develop novel therapies to overcome chemoresistance using MCJ as a target.
   
4. MCJ as an endogenous brake of mitochondrial respiration and as a target to improve CD8 cell immune response against cancer and infections. We have also identified MCJ to be abundantly expressed in CD8 cells. We have generated a number of new tools for this area, including antibodies against mouse and human MCJ, expression systems for siRNA specific for MCJ, expression vectors for MCJ and MCJ deficient mice, and more recently MCJ conditional KO mice. Our recent studies have revealed the key role of this molecule in mitochondrial metabolism in CD8 cells, and in the protective capacity of these cells against influenza virus infection. Due to the increased mitochondrial respiration, MCJ deficient CD8 cells are more efficient in producing cytokines like IFNg and they are more efficient as cytotoxic cells (Champagne et al. Immunity 2016). We are currently investigating how MCJ could be an important target to improve mitochondrial metabolism in CD8 cells as a strategy to improve vaccine efficacy and improve efficacy of cancer immunotherapy.

 

​EDUCATION

• 1986 B.S. in Biochemistry and Molecular Biology, Universidad Autonoma de Madrid, Madrid (Spain).
• 1990 Ph.D. in Immunology. Thesis entitled "Study of the role of cAMP in human T cell activation". Immunology Department, Hospital de la Princesa, Universidad Autonoma de Madrid. Madrid (Spain). 
  

ACADEMIC APPOINTMENTS

• 1995-1996 Associate Research Scientist, Laboratory of Dr. Richard A. Flavell, Section of Immunobiology, Yale University School of Medicine, New Haven, CT. 
• 1996-2002 Assistant Professor, Department of Medicine, Immunobiology Program,
  University of Vermont, Burlington, VT.
• 2002-2009 Associate Professor, Department of Medicine, Immunobiology Program University of Vermont.
• 2009-2019 Professor, Department of Medicine, Immunobiology Program, University of Vermont.
• 2019-Present  Professor Emeritus, Department of Medicine, Immunobiology Program, University of Vermont
• 2019-present Professor, Department of Immunology and Microbiology, University of Colorado at Anschutz Medical Campus
  

START-UP BIOTECH

Mitotherapeutix LLC. Co-founder and member of the Scientific Advisory Board. 

Mission: treatment of metabolic diseases (liver diseases and cancer) by targetingmitochondria.

	Felipe Valenca-Pereira, postdoctoral fellow Felipe.Pereira@cuanschutz.edu
	​Qian Fang, laboratory technician Qian.Fang@cuanschutz.edu​