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New gut associated lymphoid tissue “cryptopatches” breed murine intestinal intraepithelial T cell precursors


Numerous mouse intraepithelial T cells (IEL) bearing either TCR-αΒ or TCR-γδ have been shown to develop somewhere in the intestinal mucosa without passing through the thymus. However, just where these T cells develop has been much less clear and has remained an open question to date. In an effort to investigate this issue, we carried out immunohistochemical study on the murine gastrointestinal tract and identified numerous tiny lymphoid tissues (~1,650 tissues/intestine) in the cryptal region of the small and large intestinal mucosa except for the stomach in which clusters of c-kit+ IL-7R+ Thy1+ lympho-hemopoietic progenitors accumulated (cryptopatches). The cryptopatch cells isolated from the small intestine, which were c-kit positive (c-kit+) but lineage marker negative (Lin), gave rise to TCR-αΒ and TCR-γδ IELs following in vivo transfer or tissue engraftment into 2 Gy-irradiated severe combined immunodeficient mice. In contrast, cells isolated from Peyer’s patches and mesenteric lymph nodes, which belong in the same intestinal immune compartment but lack c-kit+Lin- cells, failed to do so. These results in conjunction with the findings of electron microscopic analysis provide direct evidence of a local intestinal T cell precursor that develops in the cryptopatches.

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  1. 1

    Pasquier LD: Evolution of the immune system: In Paul WE (ed): Fundamental Immunology. New York, NY, Raven Press, 1993, pp. 199–233.

    Google Scholar 

  2. 2

    Matsunaga T: Did the first adap-tive immunity evolve in the gut of ancient Jawed fish?. Cytogenet Cell Genet 1998;80:138–141.

    PubMed  Article  CAS  Google Scholar 

  3. 3

    Nanno M, Kanamori Y, Saito H, Miyashita MK, Shimada S, Ishi-kawa H: intestinal intraepithelial T lymphocytes. Our T cell hori-zons are expanding. Immunol Res 1998;18:41–53.

    CAS  Google Scholar 

  4. 4

    Kanamori Y, Ishimaru K, Nanno M, Maki K, Ikuta K, Nariuchi H, Ishikawa H: Identification of nov-el lymphoid tissues in murine in-testinal mucosa where clusters of c-kit+ IL-7R+ Thy1+ lympho-hemopoietic develop. J Exp Med 1996;184:1449–1459.

    PubMed  Article  CAS  Google Scholar 

  5. 5

    Rocha B,Vassali P, Guy-Grand D: The VΒ repertoire of mouse gut homodimeric α CD8+ intraepi-thelial T cell receptor α/Β+ lym-phocytes reveals a major extra-thymic pathway of T cell differ-entiation. J Exp Med 1991;173: 483–486.

    PubMed  Article  CAS  Google Scholar 

  6. 6

    Takahashi I,Kiyono H: γδ T cells: Bodyguards and/or sleepers in the gut. Chem Immunol 1998; 71:77–87.

    PubMed  CAS  Google Scholar 

  7. 7

    Lefrancois L, Puddington L: Ba-sic aspect of intraepithelial lym-phocyte immunobiology: in Ogra PL, Mestecky J, Lamm ME, Stro-ber W, Bienenstock J, McGhee JR (eds): Mucosal Immunology. San Diego, CA, Academic Press, 1999; pp. 413–428.

    Google Scholar 

  8. 8

    Klein JR: Thymus-independent development of gut T cells. Chem Immunol 1998;71:88–102.

    PubMed  CAS  Google Scholar 

  9. 9

    Huleatt JW, Lefrancois L: Anti-gen-driven induction of CD11 c on intestinal lymphocytes and CD8+ T cells in vivo. J immunol 1995; 154:5684–5693.

    PubMed  CAS  Google Scholar 

  10. 10

    Rosewald H-R, Dessing M, Dvor-ak AM, Galli SJ: Identification of a committed precursor for the mast cell lineage. Science 1996;271: 818–822.

    Article  Google Scholar 

  11. 11

    Adachi S, Yoshida H, Honda K, Maki K, Saijo K, Ikuta K, Saito T, Nishikawa S-I: Essential role of IL-7 receptor α in the formation of Peyer’s patch anlage. Int Immunol 1998;10:1–6.

    PubMed  Article  CAS  Google Scholar 

  12. 12

    Saito H, Kanamori Y, Takemori T, Nariuchi H, Kubota E, Taka-hashi-Iwanaga H, Iwanaga T, Ishi-kawa H: Generation of intestinal T cells from progenitors residing in gut cryptopatches. Science 1998; 280:275–278.

    PubMed  Article  CAS  Google Scholar 

  13. 13

    Puddington L, Olson S, LefrancoisL: Interactions between stem cell factor and c-kit are required for in-testinal immune system heme-ostasis. Immunity 1994;l:733–739.

    Article  Google Scholar 

  14. 14

    Laky K, Lefrancois L, Puddington L: Age-dependent intestinal lym-phoproliferative disorder due to stem cell factor receptor deficiency. J Immunol 1997;158:1417–1427.

    PubMed  CAS  Google Scholar 

  15. 15

    Watanabe M, Ueno Y, Yajima T, Iwao Y, Tsuchiya M, Ishikawa I, Aiso S, Hibi T, Ishii H: Interleukin 7 is produced by human intestinal epithelial cells and regulates the proliferation of intestinal mucosal lymphocyte, J Clin Invest 1995; 95:2945–2953.

    PubMed  CAS  Article  Google Scholar 

  16. 16

    Boismenu R, Havran ML: Modu-lation of epithelial cell growth by intraepithelial γδ T cells. Science 1994;266:1253–1255.

    PubMed  Article  CAS  Google Scholar 

  17. 17

    KomanoH, FujiuraY, Kawaguchi M, Matsumoto S, Hashimoto Y, Obana S, Mombaerts P, Tonegawa S, Yamammoto H, Itohara S, Nan-no M, Ishikawa H: Homeostatic regulation of intestinal epithelial by intraepithelial γδ T cells. Proc Natl Acad Sci USA 1995;92:6147–6151.

    Article  Google Scholar 

  18. 18

    Cepek KL, Shaw SK, Parker CM, Russell GJ, Morrow JS, Rimm DL, Brenner MB: Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the αEΒ7 integrin. Nature 1994;372: 190–193.

    PubMed  Article  CAS  Google Scholar 

  19. 19

    Kilshaw PJ, Karecia P: Structure and function of the mucosal T-cell integrin αEΒ7. Biochem Soc Trans 1997;25:433–439.

    CAS  Google Scholar 

  20. 20

    Higgins JM, Mandlebrot DA, Shaw SK, Russell GJ, Murphy EA, Chen Y-T, Nelson WJ, Parker CM, Bren-ner MB: Direct and regulated in-teraction of integrin αEΒ7 with E-cadherin. J Cell Biol 1998;140: 197–210.

    PubMed  Article  CAS  Google Scholar 

  21. 21

    Wang J, Whetsell M, Klein JR: Local hormone networks and in-testinal T cell homeostasis. Sci-ence 1997;275:1937–1939.

    Article  CAS  Google Scholar 

  22. 22

    Powrie F: T cells in inflammatory bowel disease: protective and path-ogenic roles. Immunity 1995;3: 171–174.

    PubMed  Article  CAS  Google Scholar 

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Correspondence to Hiromichi Ishikawa.

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Ishikawa, H., Saito, H., Suzuki, K. et al. New gut associated lymphoid tissue “cryptopatches” breed murine intestinal intraepithelial T cell precursors. Immunol Res 20, 243–250 (1999).

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Key Words

  • Cryptopatches (CP)
  • Intestinal intraepithelial T
  • lymphocyte (IEL)
  • Extrathymic T cell
  • development
  • CD8αα+T Cells