Major Histocompatibility Complex Genes: Mouse H‐2

Jiří Hatina, Charles University, Plzeň, Czech Republic

Published online: July 2008

DOI: 10.1002/9780470015902.a0004115

Mouse major histocompatibility complex genes are arranged in a complex gene cluster – the H2 complex, coding for proteins either directly performing or associated with antigen presentation to T lymphocytes. The principal level of the regulation of the expression of H2 genes is the level of transcription. The major histocompatibility complex genes are the most polymorphic genes known, both within the coding and regulatory sequences. The genetic manipulation of H2 genes is very useful for creating mouse models of human immune-related functions and pathologies. H2-associated disease susceptibility is used as a model to understand similar human diseases.

Keywords: H2 genes; transcription regulation; polymorphism; gene targeting; disease models

Figure 1. Complex H2-mediated genetic aetiology of diabetic susceptibility in nonobese diabetic (NOD) mouse. The main susceptibility locus, Idd1, has two components – the H2-Ag7 haplotype, with rather unusual presentation properties, that at the same time represents the only functional complex, because of a promoter mutation in the H2-Eb gene. In addition, a second susceptibility locus, Idd16, was mapped telomeric to the Idd1. The Idd16 seems to be complex as well, possibly involving Tnf and H2-D genes. The picture of the H2 complex was taken over from the article of Dr. RW Melvold, Major Histocompatibility Complex (MHC): Mouse, Encyclopedia of Life Sciences, DOI: 10.1038/npg.els.0003989, with the author's kind permission.
Figure 2. A comparative schema of principal regulatory elements acting on H2 class I (exemplified by H2-Kb) and class II (exemplified by H2-Ea) genes. Coding exons are represented by black boxes, introns by open boxes and untranslated regions are given in grey. Regulatory sequences that were at least partially characterized are put above the respective genes; deduced regulatory regions of the H2-Kb gene for which direct evidence is missing are put below. Not all regulatory elements must be operating in other H2 class I and class II genes. For details see text.
close
 References
    book Auchincloss H Jr., Sykes M and Sachs DH (1999) "Transplantation immunology". In: Paul WE (ed.) Fundamental Immunology, 4th edn, pp. 1175–1235. Philadelphia: Lippincott Williams & Wilkins.
    Bikoff EK, Germain R and Robertson EJ (1995) Allelic differences affecting invariant chain dependency of MHC class II subunit assembly. Immunity 2: 3011–3310.
    Carson S and Wiles MV (1993) Far upstream regions of class II MHC E are necessary for position independent, copy-dependent expression of E transgene. Nucleic Acids Research 21: 2065–2072.
    Cheuk E, D'Souza C, Hu N et al. (2002) Human MHC class I transgenic mice deficient for H2 class I expression facilitate identification and characterization of new HLA class I-restricted viral T cell epitopes. The Journal of Immunology 169: 5571–5580.
    Cosgrove D, Gray D, Dierich A et al. (1991) Mice lacking MHC class II molecules. Cell 66: 1051–1066.
    Dey A, Thornton AM, Lonergan M et al. (1992) Occupancy of upstream regulatory sites in vivo coincides with major histocompatibility complex class I gene expression in mouse tissues. Molecular and Cellular Biology 12: 359–3599.
    Drezen JM, Cohen-Tannoudji M, Pournin S, Babinet C and Morello D (1995) Developmental expression of H-2K major histocompatibility complex class I transgenes requires the presence of proximal introns. Developmental Dynamics 204: 98–105.
    Drezen JM, Nouvel P, Babinet C and Morello D (1992) Different regulation of class I gene expression in the adult mouse and during development. The Journal of Immunology 149: 429–437.
    van den Elsen PJ and Gobin SJP (1999) The common pathways of MHC class I and class II transactivation. Microbes and Infection 1: 887–892.
    van den Elsen PJ, Holling TM, Kuipers HF and van der Stoep N (2004) Transcriptional regulation of antigen presentation. Current Opinion in Immunology 16: 67–75.
    Firat H, Garcia-Pons F, Tourdot S et al. (1999) H-2 class I knockout, HLA-A2.1-transgenic mice: a versatile animal model for preclinical evaluation of antitumor immunotherapeutical strategies. The European Journal of Immunology 29: 3112–3121.
    Fujisawa T, Ikegami H, Noso S et al. (2006) MHC-linked susceptibility to type 1 diabetes in the NOD mouse. Annals of New York Academy of Sciences 1079: 118–121.
    Hamilton-Williams EE, Serreze DV, Charlton B et al. (2001) Transgenic rescue implicates 2-microglobulin as a diabetes susceptibility gene in nonobese diabetic (NOD) mice. Proceedings of the National Academy of Sciences of the USA 98: 11533–11538.
    Hatina J, Frangoulis B, Gregorová S et al. (1999) Lymphoid specificity of a copy number-related expression of the H2-Kb transgene. Molecular Immunology 36: 73–80.
    Hatina J, Jansa P and Reischig J (2002) Transcription factor NF-IL6 (C/EBP) activates the expression of the mouse MHC class I H2-Kb gene in response to TNF- via the intragenic downstream regulatory element. Journal of Interferon and Cytokine Research 22: 741–749.
    Hatina J, Králová J and Jansa P (1996) Identification of an intragenic interferon-stimulated response element sequence of the mouse class I major histocompatibility complex H-2Kb gene. Experimental and Clinical Immunogenetics 13: 55–60.
    Holling TM, Schooten E and van den Elsen PJ (2004) Function and regulation of MHC class II molecules in T-lymphocytes: of mice and men. Human Immunology 65: 282–290.
    Ikegami H, Fujisawa T, Makino S and Ogihara T (2003) Congenic mapping and candidate sequencing of susceptibility genes for type 1 diabetes in the NOD mouse. Annals of New York Academy of Sciences 1005: 1–9.
    Ishiguro N, Brown GD, Ishizu A and Meruelo D (1998) The regulation of murine H-2Dd expression by activation transcription factor 1 and cAMP response element binding protein. The Journal of Immunology 160: 5175–5184.
    Ishiguro N, Brown GD and Meruelo D (1997) Activation transcription factor 1 involvement in the regulation of murine H-2Dd expression. The Journal of Biological Chemistry 272: 15993–16001.
    Israël A, Kimura A, Fournier A, Fellous M and Kourilsky P (1986) Interferon response sequence potentiates activity of an enhancer in the promoter region of a mouse H-2 gene. Nature 322: 743–746.
    Israël A, Le Bail O, Hatat D et al. (1989) TNF stimulates expression of mouse MHC class I genes by inducing an NFB-like enhancer binding activity which displaces constitutive factors. EMBO Journal 8: 3793–3800.
    Janitz M, Reiners-Schramm L and Lauster R (1998) Expression of the H2-Ea gene is modulated by a polymorphic transcriptional enhancer. Immunogenetics 48: 266–272.
    Jansa P and Forejt J (1996) A novel type of retinoic acid response element in the second intron of the mouse H2Kb gene is activated by the RAR/RXR heterodimer. Nucleic Acids Research 24: 694–701.
    Jansa P and Hatina J (2003) The inverted CCAAT motif is an indispensable element of the Enhancer B of the mouse major histocompatibility class I H2-Kb gene. DNA and Cell Biology 22: 55–64.
    Králová J, Jansa P and Forejt J (1992) A novel downstream regulatory element of the mouse H2-Kb class I major histocompatibility gene. EMBO Journal 11: 4591–4600.
    Leiter EH (2005) Nonobese diabetic mice and the genetics of diabetes susceptibility. Current Diabetes Reports 5: 141–148.
    Lemonnier FA (2002) The utility of H-2 knockout mice. Virus Research 82: 87–90.
    Liao G, Wang J, Guo J et al. (2004) In silico genetics: identification of a functional element regulation H2-E gene expression. Science 306: 690–695.
    Madsen L, Labrecque N, Engberg J et al. (1999) Mice lacking all conventional MHC class II genes. Proceedings of the National Academy of Sciences of the USA 96: 10338–10343.
    book Margulies DH (1999) "The major histocompatibility complex". In: Paul WE (ed.) Fundamental Immunology, 4th edn, pp. 263–285. Philadelphia: Lippincott Williams & Wilkins.
    Masternak K, Peyraud N, Krawczyk M, Barras E and Reith W (2003) Chromatin remodeling and extragenic transcription at the MHC class II locus control region. Nature Immunology 4: 132–137.
    Mitchison NA and Roes J (2002) Patterned variation in murine MHC promoters. Proceedings of the National Academy of Sciences of the USA 99: 10561–10566.
    Münz C, Hofmann M, Yoshida K et al. (2002) Peptide analysis, stability studies, and structural modeling explain contradictory peptide motifs and unique properties of the NOD mouse MHC class II molecule H2-Ag7. The European Journal of Immunology 32: 2105–2116.
    Neisig A, Wubbolts R, Zang X, Melief C and Neefjes J (1996) Allele-specific differences in the interaction of MHC class I molecules with transporters associated with antigen processing. The Journal of Immunology 156: 3196–3206.
    Oaklea F, Mann J, Ruddell RG et al. (2003) Basal expression of IB is controlled by the mammalian transcription repressor RBP-J(CBF1) and its activator Notch1. The Journal of Biological Chemistry 278: 24359–24370.
    Oswald F, Liptay S, Adler G and Schmid RM (1998) NFB2 is a putative target gene of activated Notch-1 via RBP-J. Molecular and Cellular Biology 18: 2077–2088.
    book Ozato K (1995) "Control of MHC class I gene expression". In: Blair EC, Pringle CR and Maudsley DJ (eds) Modulation of MHC Antigen Expression and Diseases, pp. 81–102. Cambridge: Cambridge University Press.
    Pajot A, Michel ML, Fazilleau N et al. (2004) A mouse model of human adaptive immune functions: HLA-A2.1-/HLA-DR1-transgenic H-2 class I-/class II-knockout mice. The European Journal of Immunology 34: 3060–3069.
    Pascolo S, Bervas N, Ure JM et al. (1997) HLA-A2.1-restricted education and cytolytic activity of CD8+ T lymphocytes from 2 microglobulin (2m) HLA-A2.1 monochain transgenic H-2Db 2m double knockout mice. The Journal of Experimental Medicine 185: 2043–2051.
    Pérarnau B, Saron MF, Martin BRS et al. (1999) Single H2Kb, H2Db and H2KbDb knockout mice: peripheral CB8+ T cell repertoire and anti-lymphocytic choriomeningitis virus cytolytic responses. The European Journal of Immunology 29: 1243–1252.
    Piskurich JF, Lin KI, Lin Y et al. (2000) BLIMP-I mediates extinction of major histocompatibility class II transactivator expression in plasma cells. Nature Immunology 1: 526–532.
    Pomerleau DP, Bagley RJ, Serreze DV, Mathews C and Leiter EH (2005) Major histocompatibility complex-linked diabetes susceptibility in NOD/Lt mice. Subclonogenic analysis localizes a component of Idd16 at the H2-D end of the diabetogenic H2g7 complex. Diabetes 54: 1603–1606.
    Rohrlich PS, Cardinaud S, Firat H et al. (2003) HLA-B*0702 transgenic, H-2KbDb double-knockout mice: phenotypical and functional characterization in response to influenza virus. International Immunology 6: 765–772.
    Serreze DV, Bridget M, Chapman HD et al. (1998) Subcongenic analysis of the Idd13 locus in NOD/Lt mice: evidence for several susceptibility genes including a possible diabetogenic role for 2-microglobulin. The Journal of Immunology 160: 1472–1478.
    Shields MJ, Hodgson W and Ribaudo RK (1999) Differential association of 2 microglobulin mutants with MHC class I heavy chains and structural analysis demonstrate allele-specific interactions. Molecular Immunology 36: 561–573.
    Shirakata Y, Shuman JD and Coligan JE (1996) Purification of a novel MHC class I element binding activity from thymus nuclear extracts reveals that thymic RBP-J/CBF1 binds to NF-B-like elements. The Journal of Immunology 156: 4672–4679.
    book Sykes BC (1993) "Introduction to medical genetics". In: Royce PM and Steinmann B (eds) Connective Tissue and Its Heritable Disorders, pp. 7–50. New York: Wiley-Liss.
    Walter U, Toepfer T, Dittmar KEJ et al. (2003) Pancreatic NOD beta cells express MHC class II protein and the frequency of I-Ag7 mRNA-expressing beta cells strongly increases during progression to autoimmune diabetes. Diabetologia 46: 1106–1114.
    Yang Y and Santamaria P (2006) Lessons on autoimmune diabetes from animal models. Clinical Science 110: 627–639.
 Further Reading
    Alizadeh BZ and Koeleman BP (2008) Genetic polymorphisms in susceptibility to Type 1 Diabetes. Clinica Chimica Acta 387: 9–17.
    Ang HL and Tergaonkar V (2007) Notch and NFkappaB signaling pathways: Do they collaborate in normal vertebrate brain development and function? Bioessays 29: 1039–1047.
    Aptsiauri N, Cabrera T, Garcia-Lora A et al. (2007) MHC class I antigens and immune surveillance in transformed cells. International Review of Cytology 256: 139–189.
    Beaty JS, Sukiennicki TL and Nepom GT (1999) Allelic variation in transcription modulates MHC class II expression and function. Microbes and Infection 1: 919–927.
    van Boxel-Dezaire AH, Rani MR and Stark GR (2006) Complex modulation of cell type-specific signaling in response to type I interferons. Immunity 25: 361–372.
    book Browning M and McMichael A (eds) (1996) HLA and MHC: Genes, Molecules and Function. Oxford: BIOS Scientific Publishers.
    Chamberlain JW, Vasavada HA, Ganguly S and Weissman SM (1991) Identification of cis sequences controlling efficient position-independent tissue-specific expression of human major histocompatibility complex class I genes in transgenic mice. Molecular and Cellular Biology 11: 3564–3572.
    Chen Z, de Kauwe AL, Keech C et al. (2006) Humanized transgenic mice expressing HLA DR4-DQ3 haplotype: reconstitution of phenotype and HLA-restricted T-cell responses. Tissue Antigens 68: 210–219.
    Cheng S, Smart M, Hanson J and David CS (2003) Characterization of HLA DR2 and DQ8 transgenic mouse with a new engineered mouse class II deletion, which lacks all endogenous class II genes. Journal of Autoimmunity 21: 195–199.
    Drozina G, Kohoutek J, Jabrane-Ferrat N and Peterlin BM (2005) Expression of MHC II genes. Current Topics in Microbiology and Immunology 290: 147–170.
    Gobin SJ, van Zutphen M, Westerheide SD, Boss JM and van den Elsen PJ (2001) The MHC-specific enhanceosome and its role in MHC class I and (2)-microglobulin gene transactivation. The Journal of Immunology 167: 5175–5184.
    Gregersen JW, Holmes S and Fugger L (2004) Humanized animal models for autoimmune diseases. Tissue Antigens 63: 383–394.
    Johnson DR (2003) Locus-specific constitutive and cytokine-induced HLA class I gene expression. The Journal of Immunology 170: 1894–1902.
    book Klein J (1986) Natural History of the Major Histocompatibility Complex. New York: Wiley.
    Kushida MM, Dey A, Zhang XL et al. (1997) A 150-base pair 5¢ region of the MHC class I HLA-B7 gene is sufficient to direct tissue-specific expression and locus control region activity: the site determines efficient expression and in vivo occupancy at multiple cis-active sites throughout this region. The Journal of Immunology 159: 4913–4929.
    Lloberas J, Soler C and Celada A (1999) Mechanism of I-A gene expression. Microbes and Infection 1: 935–941.
    Maurice MM, Gould DS, Carroll J, Vugmeyster Y and Ploegh HL (2001) Positive selection of an MHC class-I restricted TCR in the absence of classical MHC class I molecules. Proceedings of the National Academy of Sciences of the USA 98: 7437–7442.
    Neumann M and Naumann M (2007) Beyond IkappaBs: alternative regulation of NF-kappaB activity. The FASEB Journal 21: 2642–2654.
    Ojcius DM, Delarbre C, Kourilsky P and Gachelin G (1994) Major histocompatibility complex class I molecules and resistance against intracellular pathogens. Critical Reviews in Immunology 14: 193–220.
    Platanias LC and Fish EN (1999) Signaling pathways activated by interferons. Experimental Hematology 27: 1583–1592.
    Roep BO (2007) Are insights gained from NOD mice sufficient to guide clinical translation? Another inconvenient truth. Annals of New York Academy of Sciences 1103: 1–10.
    Taneja V, Behrens M, Mangalam A et al. (2007) New humanized HLA-DR4-transgenic mice that mimic the sex bias of rheumatoid arthritis. Arthritis & Rheumatism 56: 69–78.
    Ting JP and Trowsdale J (2002) Genetic control of MHC class II expression. Cell 109: S21–S33.
    Vugmeyster Y, Glas R, Pé rarnau B et al. (1998) Major histocompatibility complex (MHC) class I KbDb -/- deficient mice possess functional CD8+ T cells and natural killer cells. Proceedings of the National Academy of Sciences of the USA 95: 12492–12497.
    Zheng P, Guo Y, Niu Q et al. (1998) Proto-oncogene PML controls genes devoted to MHC class I antigen presentation. Nature 396: 373–376.

Related Sub-Topics:

Major Histocompatibility Complex | Model Organisms and Human Disease
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Major Histocompatibility Complex Genes: Mouse H‐2
 
How to Cite close
Hatina, Jiří(Jul 2008) Major Histocompatibility Complex Genes: Mouse H‐2. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0004115]