Area of Research - One of the goals of Dr. Santamaria’s research program has been to test the hypothesis that white blood cells recognizing the insulin-producing beta cells of the pancreas are inactivated in individuals who are genetically resistant to diabetes. To this end, the Santamaria’s lab has genetically engineered a series of mouse strains in which most white blood cells are capable of recognizing the beta cells of the pancreas, via the so-called “T cell receptor for antigen”. These studies have provided direct information as to how white blood cells kill pancreatic beta cells, resulted in the identification of a novel protein that these white blood cells recognize to kill beta cells, and led to the identification of the key molecular “switches” that control the activation status of these beta cell-killer white blood cells. Noteworthy among these is the discovery that progression of inflammation to overt diabetes in diabetes-prone genetic backgrounds is driven by “avidity maturation” (i.e. increasing strength) of beta cell-killer white blood cell populations. Work during the past two years have shed light on the molecular basis of this “avidity maturation” process and has revealed that manipulation of this process in vivo is a useful target for therapeutic intervention. Studies of the mice engineered by Santamaria’s group has also led to the discovery of mechanisms of genetic resistance to autoimmune diabetes. Notably, Santamaria and colleagues have discovered a gene that controls the function of the so-called “regulatory” white blood cells of the immune system, whose job is to suppress immune responses. Naturally-occurring variations of this gene at the population level have dramatic effects on the anti-diabetes activity of these regulatory white blood cells. In summary, work to date has helped define genetic, biochemical and cellular mechanisms that control the development and function of beta cell-killer white blood cells. Collectively, Santamaria’s work helps define new avenues for therapeutic intervention.
Schmidt D, Verdaguer J, Averill N, Santamaria P. A mechanism for the MHC-linked resistance to autoimmunity. J Exp Med, 186:1059-1075, 1997.
Verdaguer J, Schmidt D, Anderson B, Amrani A, Santamaria P. Spontaneous autoimmune diabetes in monoclonal T-cell NOD Mice. J Exp Med, 186:1663-1676, 1997.
Amrani A, Anderson B, Verdaguer J, Bou S, Santamaria P. Perforin-independent destruction of pancreatic beta cells by diabetogenic CD8+ T cells. J Clin Invest, 103:1201-1209, 1999.
Anderson B, Park B-J, Amrani A, Verdaguer J, Bou S, Santamaria P. Prevalent CD8+ T-cell response to a single peptide/Kd complex in autoimmune diabetes. Proc Natl Acad Sci USA, 96:9311-9316, 1999.
Amrani A, Verdaguer J, Thiessen S, Bou S, Santamaria P. IL-1alpha IL-1beta and IFN-gamma mark beta cells for Fas-dependent destruction by diabetogenic CD4+ T-lymphocytes. J Clin Invest, 105:459-468, 2000.
Amrani A, Verdaguer J, Serra P, Tafuro S, Tan R, Santamaria P. Progression of autoimmune diabetes driven by avidity maturation of a T-cell population. Nature, 406:739-742, 2000.
Amrani A, Serra P, Yamanouchi J, Han B, Thiessen S, Verdaguer P and Santamaria P. CD154-dependent activation of diabetogenic CD4+ T-cells dissociated from APC activation. Immunity, 16:719-732, 2002.
Trudeau JD, Kelly-Smith C, Verchere B, Finegood DT, Santamaria P and Tan R. Autoreactive T cells in peripheral blood predict development of type 1 diabetes. J Clin Invest. 111(2):217-223, 2003.
Lieberman SM, Evans AM, Han B, Takaki T, Vinnitskaya Y, Caldwell JA, Serreze DV, Shabanowitz J, Hunt DF, Nathenson SG, Santamaria P. Identification of the novel beta cell antigen targeted by a prevalent population of pathogenic CD8+ T cells in autoimmune diabetes. Proc Natl Acad Sci USA. 100 (14) 8384-8388, 2003.
Yamanouchi J, Verdaguer J, Han B-H, Amrani A, Serra P, Santamaria P. Cross-priming of diabetogenic T-cells dissociated from CTL-induced shedding of beta cell autoantigens. J Immunol. 171:6900-6909, 2003.
Serra P, Amrani A, Yamanouchi J, Han B, Thiessen S, Utsugi T, Verdaguer P, Santamaria P. CD40 ligation releases immature dendritic cells from the control of regulatory CD4+CD25+ T-cells. Immunity. 19:877-889, 2003.
Moore A, Grimm J, Han B, Santamaria P. Tracking the recruitment of diabetogenic CD8+ T-cells to the pancreas in real time. Diabetes. 53: 1459-1466, 2004.
Han B, Serra P, Amrani A, Yamanouchi J, Maree AF, Edelstein-Keshet L, Santamaria P. Prevention of diabetes by manipulation of anti-IGRP autoimmunity: high efficiency of a low affinity altered peptide ligand. Nat Med. 11:645-652, 2005.
Han B, Serra P, Yamanouchi J, Amrani A, Elliott JF, Dickie P, Dilorenzo TP, Santamaria P. Developmental control of CD8+ T-cell avidity maturation in autoimmune diabetes. J Clin Invest. 115:1879-1887, 2005.
Walter U, Santamaria P. CD8+ T-cells in autoimmunity. Curr Opin Immunol, 17:624-631, 2005.
Maree AF, Santamaria P and Edelstein-Keshet L. Modeling competition among autoreactive CD8+ T-cells in autoimmune diabetes: Implications for antigen-specific therapy. Int Immunol. 18:1067-1077, 2006.
Yang Y, Santamaria P. T-cells and autoimmunity. In: The Autoimmune Diseases, 4th Edition. Rose NR & Mackay IR (eds). Elsevier Academic Press, 6:59-82, 2006.
Yamanouchi J, Rainbow D, Serra P, Howlett S, Hunter K, Garner VES, Gonzalez-Munoz A, Clark J, Veijola R, Cubbon R, Chen S-L, Rosa R, Cumiskey AM, Gregory S, Rogers J, Lyons PA, Healy B, Smink LJ, Todd JA, Peterson LB, Wicker LS and Santamaria P. Interleukin-2 gene variation impairs regulatory T-cell function and causes autoimmunity. Nat Genet. 39:329-337, 2007.
Tailor P, Tsai S, Shameli A, Serra P, Wang J, Robbins S, Nagata M, Szymcak-Workman AL, Vignali DA, Santamaria P. The proline-rich sequence of CD3epsilon as an amplifier of low-avidity TCR signaling. J Immunol, 181:243-255, 2008.
Tsai S, Shameli A, Santamaria P. CD8+ T-cells in type 1 diabetes. Adv Immunol, 100:79-124, 2008.
Lennon GP, Burton AR, Arnold PY, Santamaria P, Vignali DAA. T-cell islet accumulation in type 1 diabetes is a tightly-regulated, cell autonomous event. Immunity, 31:643-653, 2009.
Yamanouchi J, Serra P, Puertas M-C, Verdaguer J, Lyons P, Hunter K, Gardner V, Wicker LS, Santamaria P. The Idd9.1 locus controls the suppressive activity of FoxP3+CD4+CD25+ regulatory T-cells. Diabetes, 59(1):272-281, 2010.
Tsai S, Shameli A, Yamanouchi J, Clemente-Casares X, Wang J, Serra P, Yang Y, Medarova Z, Moore A, Santamaria P. Reversal of autoimmunity by boosting memory-like autoregulatory T-cells. Immunity, 32(4):568-580, 2010.
Santamaria P. The long and winding road to understanding and conquering type 1 diabetes. Immunity 32:437-445, 2010.
Khadra A, Tsai S, Santamaria P, Edelstein-Keshet L. On how monospecific memory-like autoregulatory CD8+ T cells can blunt diabetogenic autoimmunity: a computational approach. J Immunol, 185:5962-5972, 2010.
Wang J, Tsai S, Shameli A, Yamanouchi J, Santamaria P. In situ recognition of autoantigen as an essential gatekeeper in autoimmune CD8+ T cell inflammation. Pro Natl Acad Sci USA, 107:9317-22, 2010.
Shameli A, Clemente-Casares X, Wang J, Santamaria P. Development of memory-like autoregulatory CD8+ T cells is CD4+ T cell-dependent. J Immunol, 187:2859-2866, 2011.
Clemente-Casares X, Tsai S, Yang Y, Santamaria P. Peptide-MHC-based nanovaccines for the treatment of autoimmunity: a “one size fits all” approach? J Mol Med, 89: 733-742, 2011.
Wang J, Tsai S, Han B, Tailor P, Santamaria P. Autoantigen recognition is required for recruitment of IGRP206–214-Autoreactive CD8+ T cells but is dispensable for tolerance. J Immunol, 189: 2975-2984, 2012.
Alkemade GM, Clemente-Casares X, Yu Z, Xu BY, Wang J, Tsai S, Wright JR Jr, Roep BO, Santamaria P. Local Autoantigen Expression as Essential Gatekeeper of Memory T-cell Recruitment to Islet Grafts in Diabetic Hosts. Diabetes, 2012.
Shameli A, Yamanouchi J, Tsai S, Yang Y, Clemente-Casares X, Moore A, Serra P, Santamaria P. IL-2 promotes the function of memory-like autoregulatory CD8(+) T cells but suppresses their development via FoxP3(+) Treg cells. Eur J Immunol. 43: 394-403, 2013.
Tsai S, Serra-Devecchi P, Clemente-Casares X, Yamanouchi J, Thiessen S, Slattery RM, Elliott JF, Santamaria P. Anti-diabetogenic MHC class II promotes the differentiation of MHC-promiscuous autoreactive T-cells into FoxP3+ regulatory T cells. Proc Natl Acad Sci USA, 2013.