Specific Areas of Research Interest

The defining feature of the immune system is its ability to distinguish self from non-self. The major component of the immune system responsible for this self / non-self discrimination is the diverse repertoire of antigen-specific T lymphocytes. T cell receptors can only recognize antigens derived from pathogens or transformed cells if these antigens if the derived peptide fragments of pathogenic protieins combine with Major Histocompatibility Complex (MHC) molecules. The assembly of the antigenic peptide-MHC complex takes place in intracellular compartments, by a series of molecular events collectively referred to as "MHC-restricted antigen presentation". The research in my laboratory centers around the molecular events that regulate MHC class II-restricted antigen presentation and CD4 T cell activation in vivo. Our long term goal is to make connections between the mechanisms involved in peptide acquisition by class II molecules and those aspects of immunology that critically depend on the specific peptides presented by the class II molecule.

Specific Areas of Research Interest

1. Immunodominance in CD4 T cell responses. In specific immune responses pathogens or to protein antigens, T lymphocytes only respond to a limited number of peptide epitopes from the immunogens. These peptides are termed "immunodominant". Our experiments seek to understand the elements in vivo that dictate the narrowed selection of specificities in CD4 T cells during protective immune response, particularly pathogens such as influenza virus. One of our long-term goals is to apply the knowledge gained in animal models towards human vaccine design.
2. CD4 T cell response to influenza virus. One of our more recent areas of research is the antigen specificity and role that CD4 T cells play in the protective immune response to influenza virus. One of the major challenges in vaccine design for this pathogen is the high degree of genetic variability that occurs in different isolates, making most currently vaccines protective for only a short period of time, until a new influenza strain become prevalent in the population. Our interests focus on efforts to promote heterosubtypic immunity in the CD4 T cell compartment, by developing strategies to focus the CD4 T cells towards the most biologically active and genetically conserved epitopes.
3. Role of DM in regulating class II-restricted antigen presentation. The MHC-encoded DM molecule is now known to be a critical component of the class II presentation pathway by acting as a catalyst for peptide loading and for editing the peptide repertoire presented by class II molecules on antigen presenting cells. Our studies are aimed at understanding the molecular basis of such peptide discrimination by DM proteins and how they influence CD4 T cell activation and tolerance.
4. Molecular basis for MHC-linked autoimmunity. Genetically-determined susceptibility to autoimmune diseases is frequently associated with the expression of particular MHC class II gene products. Our laboratory is focused on delineating the structural features of MHC molecules that defects in self tolerance and induction of autoimmunity and the role that B cells play as antigen presenting cells during the induction and amplification of autoimmune responses

• Nayak JL, Fitzgerald TF, Richards KA, Yang H, Treanor JJ, Sant AJ. CD4+ T-Cell Expansion Predicts Neutralizing Antibody Responses to Monovalent, Inactivated 2009 Pandemic Influenza A(H1N1) Virus Subtype H1N1 Vaccine. J Infect Dis. 2013 Jan; 207(2):297-305.
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• Richards KA, Chaves FA, Alam S, Sant AJ. Trivalent inactivated influenza vaccines induce broad immunological reactivity to both internal virion components and influenza surface proteins. Vaccine. 2012 Dec 17; 31(1):219-25.
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• Leddon SA, Sant AJ. The Peptide specificity of the endogenous T follicular helper cell repertoire generated after protein immunization. PLoS One. 2012; 7(10):e46952.
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• Nayak JL, Sant AJ. Loss in CD4 T-cell responses to multiple epitopes in influenza due to expression of one additional MHC class II molecule in the host. Immunology. 2012 Aug; 136(4):425-36.
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• Sant AJ, McMichael A. Revealing the role of CD4+ T cells in viral immunity. J Exp Med. 2012 Jul 30; 209(8):1391-5.
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• Chaves FA, Lee AH, Nayak JL, Richards KA, Sant AJ. The utility and limitations of current web-available algorithms to predict peptides recognized by CD4 T cells in response to pathogen infection. J Immunol. 2012 May 1; 188(9):4235-48.
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• Sundararajan A, Huan L, Richards KA, Marcelin G, Alam S, Joo H, Yang H, Webby RJ, Topham DJ, Sant AJ, Sangster MY. Host differences in influenza-specific CD4 T cell and B cell responses are modulated by viral strain and route of immunization. PLoS One. 2012; 7(3):e34377.
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• Engels B, Chervin AS, Sant AJ, Kranz DM, Schreiber H. Long-term Persistence of CD4(+) but Rapid Disappearance of CD8(+) T Cells Expressing an MHC Class I-restricted TCR of Nanomolar Affinity. Mol Ther. 2012 Mar; 20(3):652-60.
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• Alam S, Sant AJ. Infection with Seasonal Influenza Virus Elicits CD4 T Cells Specific for Genetically Conserved Epitopes That Can Be Rapidly Mobilized for Protective Immunity to Pandemic H1N1 Influenza Virus. J Virol. 2011 Dec; 85(24):13310-21.
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• Richards KA, Chaves FA, Sant AJ. The memory phase of the CD4 T-cell response to influenza virus infection maintains its diverse antigen specificity. Immunology. 2011 Jun; 133(2):246-56.
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• Nayak JL, Sant AJ. T cell immunology for the clinician. Pediatr Infect Dis J. 2011 Mar; 30(3):248-50.
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• Richards KA, Topham D, Chaves FA, Sant AJ. Cutting edge: CD4 T cells generated from encounter with seasonal influenza viruses and vaccines have broad protein specificity and can directly recognize naturally generated epitopes derived from the live pandemic H1N1 virus. J Immunol. 2010 Nov 1; 185(9):4998-5002.
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• Leddon SA, Sant AJ. Generation of MHC class II-peptide ligands for CD4 T-cell allorecognition of MHC class II molecules. Curr Opin Organ Transplant. 2010 Aug; 15(4):505-11.
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• Nayak JL, Richards KA, Chaves FA, Sant AJ. Analyses of the specificity of CD4 T cells during the primary immune response to influenza virus reveals dramatic MHC-linked asymmetries in reactivity to individual viral proteins. Viral Immunol. 2010 Apr; 23(2):169-80.
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• Desmet EA, Hollenbaugh JA, Sime PJ, Wright TW, Topham DJ, Sant AJ, Takimoto T, Dewhurst S, Maggirwar SB. Mixed Lineage Kinase 3 deficiency delays viral clearance in the lung and is associated with diminished influenza-induced cytopathic effect in infected cells. Virology. 2010 May 10; 400(2):224-32.
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• Weaver JM, Chaves FA, Sant AJ. Abortive activation of CD4 T cell responses during competitive priming in vivo. Proc Natl Acad Sci U S A. 2009 May 26; 106(21):8647-52.
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• Richards KA, Chaves FA, Sant AJ. Infection of HLA-DR1 transgenic mice with a human isolate of influenza a virus (H1N1) primes a diverse CD4 T-cell repertoire that includes CD4 T cells with heterosubtypic cross-reactivity to avian (H5N1) influenza virus. J Virol. 2009 Jul; 83(13):6566-77.
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• Weaver JM, Sant AJ. Understanding the focused CD4 T cell response to antigen and pathogenic organisms. Immunol Res. 2009; 45(2-3):123-43.
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• Weaver JM, Lazarski CA, Richards KA, Chaves FA, Jenks SA, Menges PR, Sant AJ. Immunodominance of CD4 T cells to foreign antigens is peptide intrinsic and independent of molecular context: implications for vaccine design. J Immunol. 2008 Sep 1; 181(5):3039-48.
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• Huang S, Gilfillan S, Kim S, Thompson B, Wang X, Sant AJ, Fremont DH, Lantz O, Hansen TH. MR1 uses an endocytic pathway to activate mucosal-associated invariant T cells. J Exp Med. 2008 May 12; 205(5):1201-11.
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• Larkin J, Rankin AL, Picca CC, Riley MP, Jenks SA, Sant AJ, Caton AJ. CD4+CD25+ regulatory T cell repertoire formation shaped by differential presentation of peptides from a self-antigen. J Immunol. 2008 Feb 15; 180(4):2149-57.
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• Menges PR, Jenks SA, Bikoff EK, Friedmann DR, Knowlden ZA, Sant AJ. An MHC class II restriction bias in CD4 T cell responses toward I-A is altered to I-E in DM-deficient mice. J Immunol. 2008 Feb 1; 180(3):1619-33.
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• Bandyopadhyay A, Arneson L, Beeson C, Sant AJ. The relative energetic contributions of dominant P1 pocket versus hydrogen bonding interactions to peptide:class II stability: implications for the mechanism of DM function. Mol Immunol. 2008 Mar; 45(5):1248-57.
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• Gardiner A, Richards KA, Sant AJ, Arneson LS. Conformation of MHC class II I-A(g7) is sensitive to the P9 anchor amino acid in bound peptide. Int Immunol. 2007 Sep; 19(9):1103-13.
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• Sant AJ, Chaves FA, Krafcik FR, Lazarski CA, Menges P, Richards K, Weaver JM. Immunodominance in CD4 T-cell responses: implications for immune responses to influenza virus and for vaccine design. Expert Rev Vaccines. 2007 Jun; 6(3):357-68.
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• Richards KA, Chaves FA, Krafcik FR, Topham DJ, Lazarski CA, Sant AJ. Direct ex vivo analyses of HLA-DR1 transgenic mice reveal an exceptionally broad pattern of immunodominance in the primary HLA-DR1-restricted CD4 T-cell response to influenza virus hemagglutinin. J Virol. 2007 Jul; 81(14):7608-19.
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• Chaves FA, Sant AJ. Measurement of peptide dissociation from MHC class II molecules. Curr Protoc Immunol. 2007 May; Chapter 18:Unit 18.14.
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• Chaves FA, Richards KA, Torelli A, Wedekind J, Sant AJ. Peptide-binding motifs for the I-Ad MHC class II molecule: alternate pH-dependent binding behavior. Biochemistry. 2006 May 23; 45(20):6426-33.
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• Lazarski CA, Chaves FA, Sant AJ. The impact of DM on MHC class II-restricted antigen presentation can be altered by manipulation of MHC-peptide kinetic stability. J Exp Med. 2006 May 15; 203(5):1319-28.
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• Sant AJ, Chaves FA, Jenks SA, Richards KA, Menges P, Weaver JM, Lazarski CA. The relationship between immunodominance, DM editing, and the kinetic stability of MHC class II:peptide complexes. Immunol Rev. 2005 Oct; 207:261-78.
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• McFarland BJ, Katz JF, Sant AJ, Beeson C. Energetics and cooperativity of the hydrogen bonding and anchor interactions that bind peptides to MHC class II protein. J Mol Biol. 2005 Jul 1; 350(1):170-83.
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• Lazarski CA, Chaves FA, Jenks SA, Wu S, Richards KA, Weaver JM, Sant AJ. The kinetic stability of MHC class II:peptide complexes is a key parameter that dictates immunodominance. Immunity. 2005 Jul; 23(1):29-40.
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• Chaves FA, Hou P, Wu S, Sant AJ. Replacement of the membrane proximal region of I-A(d) MHC class II molecule with I-E-derived sequences promotes production of an active and stable soluble heterodimer without altering peptide-binding specificity. J Immunol Methods. 2005 May; 300(1-2):74-92.
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• Sant A, Yewdell J. Antigen processing and recognition. Curr Opin Immunol. 2003 Feb; 15(1):66-8.
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• Arneson LS, Katz JF, Liu M, Sant AJ. Hydrogen bond integrity between MHC class II molecules and bound peptide determines the intracellular fate of MHC class II molecules. J Immunol. 2001 Dec 15; 167(12):6939-46.
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• McFarland BJ, Katz JF, Beeson C, Sant AJ. Energetic asymmetry among hydrogen bonds in MHC class II*peptide complexes. Proc Natl Acad Sci U S A. 2001 Jul 31; 98(16):9231-6.
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• Nanda NK, Sant AJ. DM determines the cryptic and immunodominant fate of T cell epitopes. J Exp Med. 2000 Sep 18; 192(6):781-8.
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• Arneson LS, Peterson M, Sant AJ. The MHC class II molecule I-Ag7 exists in alternate conformations that are peptide dependent. J Immunol. 2000 Aug 15; 165(4):2059-67.
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• McFarland BJ, Sant AJ, Lybrand TP, Beeson C. Ovalbumin(323-339) peptide binds to the major histocompatibility complex class II I-A(d) protein using two functionally distinct registers. Biochemistry. 1999 Dec 14; 38(50):16663-70.
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• Sant AJ, Beeson C, McFarland B, Cao J, Ceman S, Bryant PW, Wu S. Individual hydrogen bonds play a critical role in MHC class II: peptide interactions: implications for the dynamic aspects of class II trafficking and DM-mediated peptide exchange. Immunol Rev. 1999 Dec; 172:239-53.
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• McFarland BJ, Beeson C, Sant AJ. Cutting edge: a single, essential hydrogen bond controls the stability of peptide-MHC class II complexes. J Immunol. 1999 Oct 1; 163(7):3567-71.
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• Bryant PW, Roos P, Ploegh HL, Sant AJ. Deviant trafficking of I-Ad mutant molecules is reflected in their peptide binding properties. Eur J Immunol. 1999 Sep; 29(9):2729-39.
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• Siemasko K, Eisfelder BJ, Stebbins C, Kabak S, Sant AJ, Song W, Clark MR. Ig alpha and Ig beta are required for efficient trafficking to late endosomes and to enhance antigen presentation. J Immunol. 1999 Jun 1; 162(11):6518-25.
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• Ceman S, Wu S, Jardetzky TS, Sant AJ. Alteration of a single hydrogen bond between class II molecules and peptide results in rapid degradation of class II molecules after invariant chain removal. J Exp Med. 1998 Dec 7; 188(11):2139-49.
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• Peterson M, Sant AJ. The inability of the nonobese diabetic class II molecule to form stable peptide complexes does not reflect a failure to interact productively with DM. J Immunol. 1998 Sep 15; 161(6):2961-7.
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• Tan LJ, Ceman S, Chervonsky A, Rodriguez-Paris J, Steck TL, Sant AJ. Late events in the intracellular sorting of major histocompatibility complex class II molecules are regulated by the 80-82 segment of the class II beta chain. Eur J Immunol. 1997 Jun; 27(6):1479-88.
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• Stebbins CC, Peterson ME, Suh WM, Sant AJ. DM-mediated release of a naturally occurring invariant chain degradation intermediate from MHC class II molecules. J Immunol. 1996 Dec 1; 157(11):4892-8.
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• Katz JF, Stebbins C, Appella E, Sant AJ. Invariant chain and DM edit self-peptide presentation by major histocompatibility complex (MHC) class II molecules. J Exp Med. 1996 Nov 1; 184(5):1747-53.
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• Ceman S, Sant AJ. The function of invariant chain in class II-restricted antigen presentation. Semin Immunol. 1995 Dec; 7(6):373-87.
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• Zuckerman LA, Sant AJ, Miller J. Identification of a unique costimulatory activity for murine T helper 1 T cell clones. J Immunol. 1995 May 1; 154(9):4503-12.
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• Chervonsky A, Sant AJ. In the absence of major histocompatibility complex class II molecules, invariant chain is translocated to late endocytic compartments by autophagy. Eur J Immunol. 1995 Apr; 25(4):911-8.
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• Stebbins CC, Loss GE, Elias CG, Chervonsky A, Sant AJ. The requirement for DM in class II-restricted antigen presentation and SDS-stable dimer formation is allele and species dependent. J Exp Med. 1995 Jan 1; 181(1):223-34.
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• Chervonsky AV, Gordon L, Sant AJ. A segment of the MHC class II beta chain plays a critical role in targeting class II molecules to the endocytic pathway. Int Immunol. 1994 Jul; 6(7):973-82.
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• Katz JF, Sant AJ. T cell receptor recognition of MHC class II alloantigens is highly cell type dependent. J Immunol. 1994 Feb 15; 152(4):1629-40.
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• Sant AJ, Miller J. MHC class II antigen processing: biology of invariant chain. Curr Opin Immunol. 1994 Feb; 6(1):57-63.
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• Sant AJ. Endogenous antigen presentation by MHC class II molecules. Immunol Res. 1994; 13(4):253-67.
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• Loss GE, Elias CG, Fields PE, Ribaudo RK, McKisic M, Sant AJ. Major histocompatibility complex class II-restricted presentation of an internally synthesized antigen displays cell-type variability and segregates from the exogenous class II and endogenous class I presentation pathways. J Exp Med. 1993 Jul 1; 178(1):73-85.
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• Sant AJ. Isotypic residues in the membrane proximal domain of MHC class II beta-chains control activation of CD4+ T cells. J Immunol. 1993 Jun 15; 150(12):5299-310.
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• Loss GE, Sant AJ. Invariant chain retains MHC class II molecules in the endocytic pathway. J Immunol. 1993 Apr 15; 150(8 Pt 1):3187-97.
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• Mori K, Sant A, Kohno K, Normington K, Gething MJ, Sambrook JF. A 22 bp cis-acting element is necessary and sufficient for the induction of the yeast KAR2 (BiP) gene by unfolded proteins. EMBO J. 1992 Jul; 11(7):2583-93.
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• McKisic MD, Sant AJ, Fitch FW. Some cloned murine CD4+ T cells recognize H-2Ld class I MHC determinants directly. Other cloned CD4+ T cells recognize H-2Ld class I MHC determinants in the context of class II MHC molecules. J Immunol. 1991 Nov 1; 147(9):2868-74.
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• Sant AJ, Hendrix LR, Coligan JE, Maloy WL, Germain RN. Defective intracellular transport as a common mechanism limiting expression of inappropriately paired class II major histocompatibility complex alpha/beta chains. J Exp Med. 1991 Oct 1; 174(4):799-808.
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• Lechler RI, Sant AJ, Braunstein NS, Sekaly R, Long E, Germain RN. Cell surface expression of hybrid murine/human MHC class II beta alpha dimers. Key influence of residues in the amino-terminal portion of the beta 1 domain. J Immunol. 1990 Jan 1; 144(1):329-33.
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• Sant AJ, Germain RN. Intracellular competition for component chains determines class II MHC cell surface phenotype. Cell. 1989 Jun 2; 57(5):797-805.
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• Sant AJ, Zacheis M, Rumbarger T, Giacoletto KS, Schwartz BD. Human Ia alpha- and beta-chains are sulfated. J Immunol. 1988 Jan 1; 140(1):155-60.
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• Germain RN, Sant AJ, Braunstein NS, Ronchese F. The molecular basis of antigen presentation. Princess Takamatsu Symp. 1988; 19:179-91.
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• Sant AJ, Braunstein NS, Germain RN. Predominant role of amino-terminal sequences in dictating efficiency of class II major histocompatibility complex alpha beta dimer expression. Proc Natl Acad Sci U S A. 1987 Nov; 84(22):8065-9.
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• Giacoletto KS, Sant AJ, Bono C, Gorka J, O'Sullivan DM, Quaranta V, Schwartz BD. The human invariant chain is the core protein of the human class II-associated proteoglycan. J Exp Med. 1986 Nov 1; 164(5):1422-39.
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• Sant AJ, Cullen SE, Giacoletto KS, Schwartz BD. Invariant chain is the core protein of the Ia-associated chondroitin sulfate proteoglycan. J Exp Med. 1985 Dec 1; 162(6):1916-34.
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• Sant AJ, Cullen SE, Schwartz BD. Biosynthetic relationships of the chondroitin sulfate proteoglycan with Ia and invariant chain glycoproteins. J Immunol. 1985 Jul; 135(1):416-22.
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• Sant AJ, Schwartz BD, Cullen SE. Cellular distribution of the Ia-associated chondroitin sulfate proteoglycan. J Immunol. 1985 Jul; 135(1):408-15.
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• Sant AJ, Cullen SE, Schwartz BD. Identification of a sulfate-bearing molecule associated with HLA class II antigens. Proc Natl Acad Sci U S A. 1984 Mar; 81(5):1534-8.
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• Sant AJ, Schwartz BD, Cullen SE. Identification of a new component in the murine Ia molecular complex. J Exp Med. 1983 Dec 1; 158(6):1979-92.
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