Abstract
We examined the appearance of intestinal intraepithelial lymphocytes (IEL) during the first 12 wk of life to gain insight into postnatal factors that contribute to the differences found between IEL in the large and small intestines of adult mice. Intestinal T cells were very infrequent at birth, but increased in number in the large and small intestine during the first 4 wk of life and then stabilized. The small intestinal epithelium at 2 wk of age contained mostly T cell receptor (TCR) αβ+, CD2+ T cells, unlike IEL in adult mice, which were composed of nearly equal proportions of CD2−, TCR αβ+ and TCR γδ+ cells. Between 2 and 3 wk of age, TCR γδ+, CD2− IEL increased greatly in the small intestine, whereas TCR αβ+ cells expressing CD2 decreased. By contrast, IEL in the large intestine at 2 and 3 wk of age were mostly TCR αβ+, CD2+ T cells similar to large intestinal IEL in adult mice. And finally, the expression of CD69 increased earlier and to higher levels on TCR αβ+ and TCR γδ+ IEL in the small intestine than in the large intestine. Our results demonstrate that IEL in the large and small intestine are phenotypically similar during suckling and that differences between these populations are established after weaning. Furthermore, the earlier accumulation of IEL with an activated adult IEL phenotype in the small intestine suggests that these T cells mature or expand in the gut and contribute to the maturation of immune function during postnatal life in mice.
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Abbreviations
- IEL:
-
intraepithelial lymphocytes
- LPL:
-
lamina propria lymphocytes
- LI-IEL:
-
large intestinal intraepithelial lymphocytes
- PE:
-
phycoerythrin
- SI-IEL:
-
small intestinal intraepithelial lymphocytes
- TCR:
-
T cell receptor
References
Guy-Grand D, Cerf-Bensussan N, Malissen B, Malassis-Seris M, Briottet C, Vassalli P 1991 Two gut intraepithelial CD8+ lymphocyte populations with different T cell receptors: a role for the gut epithelium in T cell differentiation. J Exp Med 173: 471–481
Lefrancois L 1991 Phenotypic complexity of intraepithelial lymphocytes of the small intestine. J Immunol 147: 1746–1751
Goodman T, Lefrancois L 1988 Expression of the γ−−δ T-cell receptor on intestinal CD8+ intraepithelial lymphocytes. Nature 333: 855–858
Goodman T, Lefrancois L 1989 Intraepithelial lymphocytes: anatomical site, not T cell receptor form, dictates phenotype and function. J Exp Med 170: 1569–1581
Mosley RL, Styre D, Klein JR 1990 CD4+CD8+ murine intestinal intraepithelial lymphocytes. Int Immunol 2: 361–365
Camerini V, Panwala C, Kronenberg M 1993 Regional specialization of the mucosal immune system: intraepithelial lymphocytes of the large intestine have a different phenotype and function than those of the small intestine. J Immunol 151: 1765–1776
Sydora B, Aranda R, Tangri S, Holcombe H, Camerini V, Castano R, Cardell S, Huse W, Peterson P, Cheroutre H, Kronenberg M 1996 Lymphocyte-epithelial cell cross talk in the intestine: do nonclassical class I molecules have a big part in the dialogue? In: Kagnoff M, Kiyono H (eds) Mucosal Immunology. Academic Press, San Diego, CA, pp 205–222.
Kilshaw PJ, Murant SJ 1990 A new surface antigen on intraepithelial lymphocytes in the intestine. Eur J Immunol 20: 2201–2202.
Van Houten NP, Mixter F, Wolfe J, Budd RC 1993 CD2 expression on murine intestinal intraepithelial lymphocytes is bimodal and defines proliferative capacity. Int Immunol 5: 665–672
Lundqvist C, Baranov V, Hammarstrom S, Athlin L, Hammarstrom ML 1995 Intra-epithelial lymphocytes: evidence for regional specialization and extrathymic T cell maturation in the human gut epithelium. Int Immunol 7: 1473–1487
Ibraghimov AR, Lynch RG 1994 Heterogeneity and biased T cell receptor α/β repertoire of mucosal CD8+ cells from murine large intestine: implications for functional state. J Exp Med 180: 433–444
Boll G, Rudolphi A, Spiess A, Reimann J 1995 Regional specialization of intraepithelial T cells in the murine small and large intestine. Scand J Immunol 41: 103–113
Boll G, Reimann J 1995 Lamina propria T cell subsets in the small and large intestine of euthymic and athymic mice. Scand J Immunol 42: 191–201
Steege JC, Buurman WA, Forget PP 1997 The neonatal development of intraepithelial and lamina propria lymphocytes in the murine small intestine. Dev Immunol 5: 121–128
Fichtelius KE, Yunis EJ, Good RA 1968 Occurrence of lymphocytes within the gut epithelium of normal and neonatally thymectomized mice. Proc Soc Exp Biol Med 128: 185–188
Lyscom N, Brueton MJ 1983 The development of intraepithelial and Peyer's patch lymphocyte sub-types in the small intestine of newborn rats. Clin Exp Immunol 54: 158–162
Lin T, Matsuzaki G, Kenai H, Nomoto K 1994 Progenies of fetal thymocytes are the major source of CD4-CD8+ αα intestinal intraepithelial lymphocytes early in ontogeny. Eur J Immunol 24: 1785–1791
Bandeira A, Itohara S, Bonneville M, Burlen-Defranoux O, Mota-Santos T, Coutinho A, Tonegawa S 1991 Extrathymic origin of intestinal intraepithelial lymphocytes bearing T-cell antigen receptor gamma delta. Proc Nat Acad Sci USA 88: 43–47
Herbst JJ, Sunshine P 1969 Postnatal development of the small intestine of the rat. Pediatr Res 3: 27–33
Al-Nafussi AI, Wright NA 1982 Cell kinetics in the mouse small intestine during immediate postnatal life. Virchows Arch 40: 51–62
Cummins AG, Steele TW, LaBrooy JT, Shearman DJC 1988 Maturation of the rat small intestine at weaning: changes in epithelial cell kinetics, bacterial flora, and mucosal immune activity. Gut 29: 1672–1679
Gordon JI, Hermiston ML 1994 Differentiation and self-renewal in the mouse gastrointestinal epithelium. Curr Opin Cell Biol 6: 795–803
Ferguson A, Parrott DMV 1972 The effect of antigen deprivation on thymus-dependent and thymus-independent lymphocytes in the small intestine of the mouse. Clin Exp Immunol 12: 477–488
Crabbe PA, Nash DR, Bazin H, Eyssen H, Heremans JF 1970 Immunohistochemical observations on lymphoid tissues from conventional and germ-free mice. Lab Invest 22: 448–457
Davies MDJ, Parrott DMV 1981 Preparation and purification of lymphocytes from the epithelium and lamina propria of murine small intestine. Gut 22: 481–488
Camerini V, Sydora BC, Aranda R, Nguyen C, MacLean C, McBride WH, Kronenberg M 1998 Generation of intestinal mucosal lymphocytes in SCID mice reconstituted with mature, thymus-derived T cells. J Immunol 160: 2608–2618
Pardoll DM, Fowlkes BJ, Bluestone JA, Kruisbeek A, Maloy WL, Coligan JE, Schwartz RH 1987 Differential expression of two distinct T-cell receptors during thymocyte development. Nature 326: 79–81
Wilson AJ, de Villartay P, MacDonald HR 1996 T cell receptor delta gene rearrangement and T early alpha (TEA) expression in immature alpha beta lineage thymocytes: implications for alpha beta/gamma delta lineage commitment. Immunity 4: 37–45
Spencer J, Dillon SB, Isaacson PG, Macdonald TT 1986 T cell subclasses in fetal human ileum. Clin Exp Immunol 65: 553–558
Howie D, Spencer J, DeLord D, Pitzalis C, Wathen NC, Dogan A, Akbar A, MacDonald TT 1998 Extrathymic T cell differentiation in the human intestine early in life. J Immunol 161: 5862–5872
Dunon D, Cooper MD, Imhof BA 1993 Thymic origin of embryonic intestinal gamma/delta T cells. J Exp Med 177: 257–263
Umesaki Y, Setoyama H, Matsumoto S, Okada Y 1993 Expansion of αβ T cell receptor-bearing intestinal intraepithelial lymphocytes after microbial colonization in germ-free mice and its independence from thymus. Immunology 79: 32–37
Bandeira A, Mota-Santos T, Itohara S, Degermann S, Heusser C, Tonegawa S, Coutinho A 1990 Localization of gamma/delta T cells to the intestinal epithelium is independent of normal microbial colonization. J Exp Med 172: 239–244
Kawaguchi-Miyashita M, Shimizu K, Nanno M, Shimada S, Watanabe T, Koga Y, Matsuoka Y, Ishikawa H, Hashimoto K, Ohwaki M 1996 Development and cytolytic function of intestinal intraepithelial T lymphocytes in antigen-minimized mice. Immunology 89: 268–273
Komano H, Fujiura Y, Kawaguchi M, Matsumoto S, Hashimoto Y, Obana S, Mombaerts P, Tonegawa S, Yamamoto H, Itohara S, Nanno M, Ishikawa H 1995 Homeostatic regulation of intestinal epithelia by intraepithelial γδ T cells. Proc Natl Acad Sci USA 92: 6147–6151
Boismenu R, Havran WL 1994 Modulation of epithelial cell growth by intraepithelial gamma delta T cells. Science 266: 1253–1255
Kim SK, Reed DS, Heath WR, Carbone F, Lefrancois L 1997 Activation and migration of CD8 T cells in the intestinal mucosa. J Immunol 159: 4295–4306
Lin T, Matsuzaki G, Kenai H, Nomoto K 1995 Extrathymic and thymic origin of murine IEL: are most IEL in euthymic mice derived from thymus?. Immunol Cell Biol 73: 469–473
Mosley RL, Styre D, Klein JR 1990 Differentiation and functional maturation of bone marrow-derived intestinal epithelial T cells expressing membrane T cell receptor in athymic radiation chimeras. J Immunol 145: 1369–1375
Poussier P, Edouard P, Lee C, Binnie M, Julius M 1992 Thymus-independent development and negative selection of T cells expressing T cell receptor α/β in the intestinal epithelium: evidence for distinct circulation patterns of gut- and thymus-derived T lymphocytes. J Exp Med 176: 187–199
Rocha B, Vassalli P, Guy-Grand D 1994 Thymic and extrathymic origins of gut intraepithelial lymphocyte populations in mice. J Exp Med 180: 681–686
Acknowledgements
The authors thank Dr. Mitchell Kronenberg for advice and careful reading of the manuscript, Katherine Williams (UCLA) and William Ross (University of Virginia) for flow cytometry data acquisition and analysis, Marcia Bentz and Erin Tobias for preparing frozen tissue sections (University of Virginia), and Xiao Ming Wang for technical assistance (University of Virginia).
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Supported by grants from the Robert Wood Johnson Foundation (V.C.), NIH predoctoral training grant GM07185 (C.P.), and Individual National Research Service Award DK09332 (P.H.).
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Kuo, S., El Guindy, A., Panwala, C. et al. Differential Appearance of T Cell Subsets in the Large and Small Intestine of Neonatal Mice. Pediatr Res 49, 543–551 (2001). https://doi.org/10.1203/00006450-200104000-00017
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DOI: https://doi.org/10.1203/00006450-200104000-00017
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