Gustavo J. Martinez, PhD
In this section
Gustavo Martinez earned his M.Sc. degree at the University of Buenos Aires, School of Natural and Exact Sciences in Argentina. He studied the role of costimulatory molecules on T cells in patients with Mycobacterium infections (tuberculosis and leprosy).
In 2006, Gustavo moved to the United States to earn his Ph.D. in the laboratory of Dr. Chen Dong. Gustavo’s research at the time focused on understanding the molecular mechanisms underlying the transcriptional regulation of T helper 17 and regulatory T cells. In particular, he focused on the role of the Treg master transcription factor Foxp3 in Th17 cell differentiation, and the importance of the Smad-dependent branch of TGF-beta signaling in Th17/Treg differentiation. He also collaborated in other projects elucidating the mechanisms driving Th17, regulatory T and follicular helper T cells generation.
In 2011, Dr. Martinez joined the laboratory of Dr. Anjana Rao and Dr. Patrick Hogan. As a Jane Coffin Childs Memorial Fund fellow, Dr. Martinez investigated the role of the Nuclear Factor of Activated T cell (NFAT) family of transcription factors in both CD4 and CD8 T cell responses to viral infection, as well as the role of NFAT in the generation of hyporesponsive states in T cells upon deficiency in binding to its partner AP-1 transcription factor. Dr. Martinez showed that NFAT transcription factors can drive the generation of follicular helper T cells upon acute viral infection, and also demonstrated an important role of NFAT1 in the generation of exhaustion-associated genes.
The overall goal of the laboratory is to understand how NFAT family members achieve binding site selectivity in cis-acting regulatory DNA in vivo to mediate their specific and overlapping transcriptional programs during the activation and differentiation of T lymphocytes. The molecular basis for how transcriptional specificity within members of the same family is achieved is unclear and a central question throughout mammalian biology. The following research projects are ongoing in the laboratory:
Crucial role of NFAT family members in T cell exhaustion. In the face of chronic infections (persistent antigen stimulation), antigen-specific CTLs show a gradual decrease in effector function, a phenomenon that has been termed CD8+ T cell “exhaustion”. CD8+ T cell exhaustion has been observed in patients with HIV, HBV, and HCV infections, as well as in several forms of cancer. While the phenotype of these cells has been described, the molecular mechanisms that lead to their generation remain unclear. I showed that NFAT transcription factors play important roles in CD8+ T cell exhaustion. I found that NFAT family members are crucial for induction of several exhausted-associated genes, using RNA-seq and ChIP-seq approaches as well as in vivo bacterial infection and tumor models (Martinez GJ et al, 2015). These results highlight the importance of NFAT family members not only in T cell activation but also in the generation of hyporesponsive states, which need to be reverted in chronic infections and in anti-tumor responses. Our studies are now focused at understanding how NFAT transcription factors, by cooperating with other transcription factor partners in distinct genomic loci, can achieve binding site and gene regulation specificity.
NFAT family members are required for the generation of follicular helper T cells in acute viral infection. Follicular helper CD4+ T (Tfh) cells are essential for mediating B cell help, and inducing germinal center responses required for most high affinity antibody responses. Tfh cells have been characterized by their expression of chemokine (C-X-C motif) receptor 5 (CXCR5) and the lineage-defining transcription factor B-Cell CLL/Lymphoma 6 (Bcl6). Bcl6 does not act alone, and other transcription factors have also been identified as key regulators of Tfh differentiation, including STATs, Maf, BATF, IRF4, ASCL2, and LEF-1 and TCF-1. NFAT2 is highly expressed in Tfh cells, however the roles played by NFAT family members in Tfh cells are not well understood. Dr. Martinez recently showed that deficiency in NFAT1 and NFAT2 in CD4+ T cells leads to impaired germinal center reactions upon viral infection due to reduced Tfh cell differentiation and defective expression of proteins involved in T:B interactions and B cell help, including ICOS, PD-1, and SLAM family receptors (Martinez GJ et al. 2016). NFAT proteins are important TCR and Ca2+-dependent regulators of T cell biology, and Dr. Martinez now demonstrated a major positive role of NFAT family members in Tfh differentiation. The laboratory will now focus on further understanding how NFAT transcription factor family members, and in particular NFAT2, drive the generation of follicular helper T cells by regulating specific gene expression.
Role of NFAT transcription factors in CTL differentiation and function. Cytotoxic T lymphocytes (CTLs) are crucial for protection against viral and intracellular bacterial infections as well as in cancer. Moreover, generation of CTL memory responses is one of the ultimate goals of vaccine development. In Dr. Rao’s lab, I focused on understanding the role of NFAT transcription factors in transcriptional elongation in memory-like CD8+ T cells and in their role in CTL differentiation. I demonstrated that NFAT family members play non-redundant and even opposing roles in the commitment of naïve CD8+ T cells to effector and memory cells. The laboratory will focus and further determining the independent contribution of different family members in CTL biology.
Martinez GJ*, Hu JK, Pereira RM, Crampton JS, Togher S, Bild N, Crotty S, and Rao A. Cutting Edge: NFAT transcription factors promote the generation of follicular helper T cells in response to acute viral infection. J. Immunol. 2016. In press. # corresponding author.
Martinez GJ*, Pereira RM*, Äijö T*, Kim EY, Marangoni F, Pipkin ME, Togher S, Heissmeyer V, Zhang YC, Crotty S, Lamperti ED, Ansel KM, Mempel TR, Lähdesmäki H, Hogan PG, and Rao A. The transcription factor NFAT promotes exhaustion of activated CD8+ T cells. Immunity. 2015 Feb 17;42(2):265-78.
Tanaka S, Tanaka K, Magnusson F, Chung Y, Martinez GJ, Wang YH, Nurieva RI, Kurosaki T, Dong C. CCAAT/enhancer-binding protein α negatively regulates IFN-γ expression in T cells. J Immunol. 2014 Dec 15;193(12):6152-60.
Pereira RM, Martinez GJ, Engel I, Cruz-Guilloty F, Barboza BA, Tsagaratou A, Lio CW, Berg LJ, Lee Y, Kronenberg M, Bandukwala HS, and Rao A. Jarid2 is induced by TCR signaling and controls iNKT cell maturation. Nat Commun. 2014 Aug 8;5:4540. doi: 10.1038/ncomms5540.
Trifari S, Pipkin ME, Bandukwala HS, Aijö T, Bassein J, Chen R, Martinez GJ, and Rao A. MicroRNA-directed program of cytotoxic CD8+ T-cell differentiation. Proc Natl Acad Sci U S A. 2013 Nov 12;110(46):18608-13.
Wang A, Pan D, Lee YH, Martinez GJ, Feng XH, and Dong C. Cutting Edge: Smad2 and Smad4 Regulate TGF-β-Mediated Il9 Gene Expression via EZH2 Displacement. J Immunol. 2013 Nov 15;191(10):4908-12.
Chung Y, Yamazaki T, Kim B-S, Zhang Y, Reynolds JM, Martinez GJ, Chang SH, Lim H, Birkenbach M, and Dong C. Epstein Barr virus-Induced 3 (EBI3) together with IL-12 negatively regulates T helper 17-mediated immunity to Listeria monocytogenes infection. PLOS Pathogens. 2013. 9 (9), e1003628.
Martinez GJ and Rao A. Cooperative Transcription Factor Complexes in Control. Science. 2012. 338 (6109): 891-892.
Reynolds JM, Martinez GJ, Nallaparaju KC, Chang SH and Dong C. Cutting Edge: Regulation of intestinal inflammation and barrier function by IL-17C. J. Immunol. 2012. 189(9):4226-3.
Reynolds JM, Martinez GJ, Chung Y and Dong C. Toll-like receptor 4 signaling in T cells promotes autoimmune inflammation. Proc Natl Acad Sci U S A. 2012. 109(32):13064-9.
Jurado JO, Pasquinelli V, Alvarez IB, Martinez GJ, Laufer N, Sued O, Cahn P, Musella RM, Abbate E, Salomón H and Quiroga MF. ICOS, SLAM and PD-1expression and regulation on T lymphocytes reflect the immune dysregulation in AIDS patients with pulmonary tuberculosis. J. Int. AIDS Soc. 2012. 5(2):17428.
Chang SH*, Reynolds JM*, Pappu BP, Chen G, Martinez GJ and Dong C. Interleukin-17C promotes Th17 cell responses and autoimmune disease via interleukin-17 receptor E. Immunity. 2011. 35(4): 611-621.
Li HS, Gelbard A, Martinez GJ, Esashi E, Zhang H, Nguyen-Jackson H, Liu YJ, Overwijk WW and Watowich SS. Cell intrinsic role for interferon-alpha-STAT1 signals in regulating murine Peyer's Patch plasmacytoid dendritic cells and conditioning an inflammatory response. Blood. 2011. 118(14):3879-89.
Chung Y, Tanaka S, Chu F, Nurieva RI, Martinez GJ, Rawal S, Wang YH, Lim H, Reynolds JM, Zhou XH, Fan HM, Liu ZM, Neelapu SS and Dong C. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat. Med. 2011. 17(8):983-8.
Martinez GJ, Zhang Z, Reynolds JM, Tanaka S, Chung Y, Liu T, Robertson E, Lin X, Feng XH and Dong C. Smad2 positively regulates the generation of Th17 cells. J. Biol. Chem. 2010. 285(38):29039-43.
Reynolds JM, Pappu BP, Peng J, Martinez GJ, Zhang Y, Chung Y, Ma L, Yang XO, Nurieva RI, Tian Q and Dong C. Toll-like Receptor 2 Signaling in CD4+ T Lymphocytes Promotes T Helper 17 Responses and Regulates the Pathogenesis of Autoimmune Disease. Immunity. 2010. 32(5): 692-702.
Nurieva RI*, Zheng S*, Jin W, Chung Y, Zhang Y, Martinez GJ, Reynolds JM, Wang SL, Lin X, Sun SC, Lozano G and Dong C. The E3 Ubiquitin Ligase GRAIL Regulates T Cell Tolerance and Regulatory T Cell Function by Mediating T Cell Receptor-CD3 Degradation. Immunity. 2010. 32(5): 670-68.
Martinez GJ, Zhang Z, Chung Y, Reynolds JM, Lin X, Jetten A, Feng XH and Dong C. Smad3 differentially regulates the induction of regulatory and inflammatory T cell differentiation. J. Biol. Chem. 2009. 284(51):35283-6.
Martinez GJ and Dong C. BATF: Bringing (in) Another Th17-regulating Factor. J. Mol. Cell Biol. 2009. 1(2):66-8.
Nurieva RI, Chung Y, Martinez GJ, Yang XO, Tanaka S, Matskevitch TD, and Dong C. Bcl6 mediates the development of T follicular helper cells. Science. 2009. 325:1001-1005.
Chung Y, Chang SH, Martinez GJ, Yang XO, Nurieva R, Kang HS, Ma L, Watowich SS, Jetten AM, Tian Q, Dong C. Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity. 2009. 30(4):576-87.
Martinez GJ, Nurieva RI, Yang XO and Dong C. Regulation and function of pro-inflammatory TH17 cells. Ann. N. Y. Acad. Sci. 2008. 1143, pp. 188-211.
Yang XO*, Nurieva R*, Martinez GJ*, Kang HS, Chung Y, Pappu BP, Shah B, Chang SH, Schluns KS, Watowich SS, Feng XH, Jetten AM, Dong C. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity. 2008. 29(1):44-56.
Jurado JO, Alvarez IB, Pasquinelli V, Martínez GJ, Quiroga MF, Abbate E, Musella RM, Chuluyan HE and García VE. 2008. PD-1:PD-L1/PD-L2 pathway inhibits T cell effector functions during human tuberculosis. J. Immunol. 2008. 181(1):116-25.
Quiroga MF, Jurado JO, Martínez GJ, Pasquinelli V, Musella RM, Abbate E, Issekutz AC, Bracco MM, Malbran A, Sieling PA, Chuluyan E, García VE. Cross-talk between CD31 and the signaling lymphocytic activation molecule-associated protein during interferon- gamma production against Mycobacterium tuberculosis. J. Infect. Dis. 2007. 196(9):1369-78.
Nurieva R, Yang XO, Martinez GJ, Zhang Y, Panopoulos AD, Ma L, Schluns K, Tian Q, Watowich SS, Jetten AM, Dong C. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature. 2007. 448(7152):480-3.
Quiroga MF*, Pasquinelli V*, Martínez GJ, Jurado JO, Castro Zorrilla L, Musilla RM, Abbate E, Sieling PA, García VE. Inducible Costimulator (ICOS): a modulator of IFN-γ production in human tuberculosis. J. Immunol. 2006. 176: 5965-74.
Quiroga MF, Martínez GJ, Pasquinelli V, García VE. La proteína asociada a SLAM (SAP) regula la expresión de IFN-γ en lepra. Medicina, Buenos Aires. 2004. 64:436-438.
Quiroga MF, Martínez GJ, Pasquinelli V, Costas MA, Bracco MM, Malbrán A, Olivares LM, Sieling PA, García VE. Activation of Signaling Lymphocytic Activation Molecule triggers a signaling cascade that enhances Th1 responses in human intracellular infection. J. Immunol. 2004. 173: 4120-4129.
Pasquinelli V, Quiroga MF, Martínez GJ, Castro Zorrilla L, Mussella RM, Bracco MM, Belmonte L, Malbrán A, Fainboim L, Sieling PA, García VE. Expression of SLAM associated protein (SAP) interrupts IFN-γ production in human tuberculosis. J. Immunol. 2004. 172: 1177-1185.