Lymphocytes: Intraepithelial

Intraepithelial lymphocytes (IEL) are small, round mononuclear immune cells, which reside in the paracellular space between nonimmune epithelial cells. They are found in the skin and within the epithelial layer that lines the intestine, the biliary tract, the oral cavity, the upper respiratory tract and lungs and the reproductive tract. The largest population of IEL resides within the epithelium of the small intestine where they form the first line of immune defence against invading pathogens while preserving the integrity of the mucosal barrier.

Key concepts

  • The lymphocytes located in the epithelium are at the frontline between the self and nonself.
  • The T-cell populations from the small intestine are the most important in number and the most diverse in the body.
  • The T-cell populations from the epithelium often contain unconventional subpopulation such as CD8aa TCRab+ IEL in the intestine.
  • Introduction of the new concept of agonist selection for self-specific CD8aa TCRab+ IEL.
  • Important function of IEL during immune response against pathogens.

Keywords: ; T cell; ; T cell; CD8; cytotoxic T cell; cytokine; agonist selection

Figure 1. (a) Villi architecture of the small intestinal epithelium in mouse. Hematoxyline-Eosin staining. (b) T cells in the villi of normal human small intestine. Note the high density of T cells (intraepithelial lymphocytes) are basolaterally situated in the epithelial layer. Immunoperoxidase with anti-CD3, original magnification ×100.
Figure 2. Schema summarizing the differentiation of type a and b IEL. CD4 and CD8 TCRab differentiate in the thymus through a CD4+ CD8+ (DP) stage. CD4 and CD8+ mature T cells leave the thymus to colonize peripheral lymphoid tissue where they stay as naïve T cells. Under antigenic stimulation they will differentiate into effector T cells and gain the capacity to migrate to the intestinal epithelium. CD8 TCR differentiate in the thymus through the CD4 CD8 CD8 (TP) stage and later CD4– CD8– (DN) TCR+. DN TCR+ egress the thymus and reach the small intestine epithelium where they express CD8 under IL-15 to become CD8 TCR IEL. Finally CD8 TCR IEL develop from CD4– CD8– (DN) precursors.
Figure 3. Schematic representation of the recognition elements of TCR IEL cells on the surface of normal and infected epithelial cells. Normal epithelial cells in the small intestine express low level of MICA and MICB. The expression of these molecules is upregulated during inflammation and/or infections by a heat shock response element promoter. When high levels of MICA or MICB are expressed, TCR is engaged and the T cell kills the epithelial cell. This mechanism must be efficient for the elimination of infected epithelial cells.
close
 References
    Arstila T, Arstila TP, Calbo S et al. (2000) Identical T cell clones are located within the mouse gut epithelium and lamina propia and circulate in the thoracic duct lymph. Journal of Experimental Medicine 191: 823–834.
    Balk SP, Ebert EC, Blumenthal RL et al. (1991) Oligoclonal expansion and CD1 recognition by human intestinal intraepithelial lymphocytes. Science 253: 1411–1415.
    Bandeira A, Itohara S, Bonneville M et al. (1991) Extrathymic origin of intestinal intraepithelial lymphocytes bearing T-cell antigen receptor gamma delta. Proceedings of the National Academy of Sciences of the USA 88: 43–47.
    Bauer S, Groh V, Wu J et al. (1999) Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285: 727–729.
    Bhagat G, Naiyer AJ, Shah JG et al. (2008) Small intestinal CD8+TCRgammadelta+NKG2A+ intraepithelial lymphocytes have attributes of regulatory cells in patients with celiac disease. Journal of Clinical Investigation 118: 281–293.
    Boyden LM, Lewis JM, Barbee SD et al. (2008) Skint1, the prototype of a newly identified immunoglobulin superfamily gene cluster, positively selects epidermal gammadelta T cells. Nature Genetics 40: 656–662.
    Cerwenka A, Bakker AB, McClanahan T et al. (2000) Retinoic acid early inducible genes define a ligand family for the activating NKG2D receptor in mice. Immunity 12: 721–727.
    Cheroutre H and Lambolez F (2008) Doubting the TCR coreceptor function of CD8alphaalpha. Immunity 28: 149–159.
    Cheroutre H and Madakamutil L (2004) Acquired and natural memory T cells join forces at the mucosal front line. Nature Reviews. Immunology 4: 290–300.
    Denning TL, Granger SW, Mucida D et al. (2007) Mouse TCRalphabeta+CD8alphaalpha intraepithelial lymphocytes express genes that down-regulate their antigen reactivity and suppress immune responses. Journal of Immunology 178: 4230–4239.
    Diefenbach A, Jamieson AM, Liu SD, Shastri N and Raulet DH (2000) Ligands for the murine NKG2D receptor: expression by tumor cells and activation of NK cells and macrophages. Nature Immunology 1: 119–126.
    Fujiura Y, Kawaguchi M, Kondo Y et al. (1996) Development of CD8 alpha alpha+ intestinal intraepithelial T cells in beta 2-microglobulin- and/or TAP1-deficient mice. Journal of Immunology 156: 2710–2715.
    Gangadharan D, Lambolez F, Attinger A et al. (2006) Identification of pre- and postselection TCRalphabeta+ intraepithelial lymphocyte precursors in the thymus. Immunity 25: 631–641.
    Gapin L, Cheroutre H and Kronenberg M (1999) Cutting edge: TCR alpha beta+ CD8 alpha alpha+ T cells are found in intestinal intraepithelial lymphocytes of mice that lack classical MHC class I molecules. Journal of Immunology 163: 4100–4104.
    Goodman T and Lefrancois L (1988) Expression of the gamma-delta T-cell receptor on intestinal CD8+ intraepithelial lymphocytes. Nature 333: 855–858.
    Goodman T and Lefrancois L (1989) Intraepithelial lymphocytes. Anatomical site, not T cell receptor form, dictates phenotype and function. Journal of Experimental Medicine 170: 1569–1581.
    Groh V, Steinle A, Bauer S and Spies T (1998) Recognition of stress-induced MHC molecules by intestinal epithelial gammadelta T cells. Science 279: 1737–1740.
    Guy-Grand D, Cerf-Bensussan N, Malissen B et al. (1991) Two gut intraepithelial CD8+ lymphocyte populations with different T cell receptors: a role for the gut epithelium in T cell differentiation. Journal of Experimental Medicine 173: 471–481.
    Guy-Grand D, Cuenod-Jabri B, Malassis-Seris M, Selz F and Vassalli P (1996) Complexity of the mouse gut T cell immune system: identification of two distinct natural killer T cell intraepithelial lineages. European Journal of Immunology 26: 2248–2256.
    Guy-Grand D, Pardigon N, Darche S et al. (2001) Contribution of double-negative thymic precursors to CD8alpha alpha (+) intraepithelial lymphocytes of the gut in mice bearing TCR transgenes. European Journal of Immunology 31: 2593–2602.
    Guy-Grand D, Rocha B, Mintz P et al. (1994) Different use of T cell receptor transducing modules in two populations of gut intraepithelial lymphocytes are related to distinct pathways of T cell differentiation. Journal of Experimental Medicine 180: 673–679.
    Hayday A, Theodoridis E, Ramsburg E and Shires J (2001) Intraepithelial lymphocytes: exploring the Third Way in immunology. Nature Immunology 2: 997–1003.
    Hayday AC (2000) [gamma][delta] cells: a right time and a right place for a conserved third way of protection. Annual Review of Immunology 18: 975–1026.
    Holtmeier W, Witthoft T, Hennemann A, Winter HS and Kagnoff MF (1997) The TCR-delta repertoire in human intestine undergoes characteristic changes during fetal to adult development. Journal of Immunology 158: 5632–5641.
    Howie D, Spencer J, DeLord D et al. (1998) Extrathymic T cell differentiation in the human intestine early in life. Journal of Immunology 161: 5862–5872.
    Hue S, Mention JJ, Monteiro RC et al. (2004) A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity 21: 367–377.
    Ke Y, Pearce K, Lake JP, Ziegler HK and Kapp JA (1997) Gamma delta T lymphocytes regulate the induction and maintenance of oral tolerance. Journal of Immunology 158: 3610–3618.
    Lambolez F, Kronenberg M and Cheroutre H (2007) Thymic differentiation of TCR alpha beta(+) CD8 alpha alpha(+) IELs. Immunological Review 215: 178–188.
    Lefrancois L and Goodman T (1989) In vivo modulation of cytolytic activity and Thy-1 expression in TCR-gamma delta+ intraepithelial lymphocytes. Science 243: 1716–1718.
    Lefrancois L and Puddington L (2006) Intestinal and pulmonary mucosal T cells: local heroes fight to maintain the status quo. Annual Review of Immunology 24: 681–704.
    Leishman AJ, Gapin L, Capone M et al. (2002) Precursors of functional MHC class I- or class II-restricted CD8alphaalpha(+) T cells are positively selected in the thymus by agonist self-peptides. Immunity 16: 355–364.
    Lepage AC, Buzoni-Gatel D, Bout DT and Kasper LH (1998) Gut-derived intraepithelial lymphocytes induce long term immunity against Toxoplasma gondii. Journal of Immunology 161: 4902–4908.
    Lewis JM, Girardi M, Roberts SJ et al. (2006) Selection of the cutaneous intraepithelial gammadelta+ T cell repertoire by a thymic stromal determinant. Nature Immunology 7: 843–850.
    Lin T, Matsuzaki G, Yoshida H et al. (1994) CD3-CD8+ intestinal intraepithelial lymphocytes (IEL) and the extrathymic development of IEL. European Journal of Immunology 24: 1080–1087.
    Lin T, Yoshida H, Matsuzaki G et al. (1999) Autospecific gammadelta thymocytes that escape negative selection find sanctuary in the intestine. Journal of Clinical Investigation 104: 1297–1305.
    Mowat AM (2003) Anatomical basis of tolerance and immunity to intestinal antigens. Nature Reviews. Immunology 3: 331–341.
    Mucida D, Park Y, Kim G et al. (2007) Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317: 256–260.
    Neuhaus O, Emoto M, Blum C, Yamamoto S and Kaufmann SH (1995) Control of thymus-independent intestinal intraepithelial lymphocytes by beta 2-microglobulin. European Journal of Immunology 25: 2332–2339.
    Ohno H, Ono S, Hirayama N, Shimada S and Saito T (1994) Preferential usage of the Fc receptor gamma chain in the T cell antigen receptor complex by gamma/delta T cells localized in epithelia. Journal of Experimental Medicine 179: 365–369.
    Park SH, Guy-Grand D, Lemonnier FA et al. (1999) Selection and expansion of CD8alpha/alpha(1) T cell receptor alpha/beta(1) intestinal intraepithelial lymphocytes in the absence of both classical major histocompatibility complex class I and nonclassical CD1 molecules. Journal of Experimental Medicine 190: 885–890.
    Pennington DJ, Silva-Santos B, Shires J et al. (2003) The inter-relatedness and interdependence of mouse T cell receptor gammadelta+ and alphabeta+ cells. Nature Immunology 4: 991–998.
    Poussier P, Edouard P, Lee C, Binnie M and Julius M (1992) Thymus-independent development and negative selection of T cells expressing T cell receptor alpha/beta in the intestinal epithelium: evidence for distinct circulation patterns of gut- and thymus-derived T lymphocytes. Journal of Experimental Medicine 176: 187–199.
    Poussier P, Ning T, Banerjee D and Julius M (2002) A unique subset of self-specific intraintestinal T cells maintains gut integrity. Journal of Experimental Medicine 195: 1491–1497.
    Roberts SJ, Smith AL, West AB et al. (1996) T-cell alpha beta+and gamma delta+deficient mice display abnormal but distinct phenotypes toward a natural, widespread infection of the intestinal epithelium. Proceedings of the National Academy of Sciences of the USA 93: 11774–11779.
    Rocha B, Vassalli P and Guy-Grand D (1991) The V beta repertoire of mouse gut homodimeric alpha CD8+ intraepithelial T cell receptor alpha/beta+lymphocytes reveals a major extrathymic pathway of T cell differentiation. Journal of Experimental Medicine 173: 483–486.
    Saito H, Kanamori Y, Takemori T et al. (1998) Generation of intestinal T cells from progenitors residing in gut cryptopatches. Science 280: 275–278.
    Saurer L, Seibold I, Rihs S et al. (2004) Virus-induced activation of self-specific TCR alpha beta CD8 alpha alpha intraepithelial lymphocytes does not abolish their self-tolerance in the intestine. Journal of Immunology 172: 4176–4183.
    Schluns KS, Nowak EC, Cabrera-Hernandez A et al. (2004) Distinct cell types control lymphoid subset development by means of IL-15 and IL-15 receptor alpha expression. Proceedings of the National Academy of Sciences of the USA 101: 5616–5621.
    Sydora BC, Brossay L, Hagenbaugh A, Kronenberg M and Cheroutre H (1996) TAP-independent selection of CD8+ intestinal intraepithelial lymphocytes. Journal of Immunology 156: 4209–4216.
    Williams AM, Bland PW, Phillips AC et al. (2004) Intestinal alpha beta T cells differentiate and rearrange antigen receptor genes in situ in the human infant. Journal of Immunology 173: 7190–7199.
    Zhao H, Nguyen H and Kang J (2005) Interleukin 15 controls the generation of the restricted T cell receptor repertoire of gamma delta intestinal intraepithelial lymphocytes. Nature Immunology 6: 1263–1271.
 Further Reading
    Agace WW (2008) T-cell recruitment to the intestinal mucosa. Trends in Immunology 29: 514–522.
    Artis D (2008) Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nature Reviews. Immunology 8: 411–420.
    Holt PG, Strickland DH, Wikström ME and Jahnsen FL (2008) Regulation of immunological homeostasis in the respiratory tract. Nature Reviews. Immunology 8, 142–152.
    Jameson J and Havran WL (2007) Skin gammadelta T-cell functions in homeostasis and wound healing. Immunological Reviews 215: 114–122.
    Johansson-Lindbom B and Agace WW (2007) Generation of gut-homing T cells and their localization to the small intestinal mucosa. Immunological Reviews 215: 226–242.
    McGhee JR, Kunisawa J and Kiyono H (2007) Gut lymphocyte migration: we are halfway ‘home’. Trends in Immunology 28: 150–153.
    Nanno M, Shiohara T, Yamamoto H, Kawakami K and Ishikawa H (2007) gammadelta T cells: firefighters or fire boosters in the front lines of inflammatory responses. Immunological Reviews 215: 103–113.
    Xiong N and Raulet DH (2007) Development and selection of gammadelta T cells. Immunological Reviews 215: 15–31.
    Yamagata T, Benoist C and Mathis D (2006) A shared gene-expression signature in innate-like lymphocytes. Immunological Reviews 210: 52–66.
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Cheroutre, Hilde, and Lambolez, Florence(Mar 2009) Lymphocytes: Intraepithelial. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001197.pub2]