Intraepithelial lymphocyte

Intraepithelial lymphocytes (IEL) are

Intestinal IELs are long-lived resistant effector cells spread along the entire length of intestine, where they patrol the space between intestinal epithelial cells (IEC) and the basement membrane (the intraepithelial space). Epithelium of small intestine contains approximately 1 IEL per 10 enterocytes.^[3] Due to their constant exposure to of antigens at mucosal barrier, they have unique antigen-experienced activated phenotypes and they constantly express CD103 (αE integrin), that is distinct from the conventional T cells in the intestine.^[3] IELs are mainly T cells with mixture of subsets. They are divided into two groups – conventional and unconventional IELs.^[4]

In mice both groups are retained in almost equal proportions.^[5] In humans, the majority of IELs are alpha beta T cells. 15% of IELs are gamma delta T cells and thus represent a minor component of human IELs. However, IELs significantly increase under certain conditions, such as celiac disease.^[1]

Phenotype

The majority of IELs (80%) are CD3+, and over 75% of these also express CD8. IELs can be divided into two major subsets based on their CD8 coreceptor expression.^[5] One subset of IELs typically express activation marker CD8αα and some IELs express CD8αβ⁺ marker (CD8αβ promotes TCR activation, whereas CD8αα suppresses TCR signals).

In both humans and mice IELs express higher levels of

CD8αα can also recognize thymus leukemia (TL) antigen, which is a non-classical MHC I molecule that is expressed in thymus and in intestinal epithelium. Interaction between TL and CD8αα does not serve for migration of IELs into the epithelium, but it is important for modulating immune response of IELs.^[9] It has been suggested that cross-talk between TL and CD8αα might regulate IELs survival and proliferation.^[8] More accurately, TL prevents proliferation of IELs, when there is co-occurrence of weak TCR stimulation.^[9]

Development

Induced IELs (TCRαβ+ CD8αβ⁺) are generated from naive T cells during an immune response. TCRαβ⁺ CD8αα (natural IELs) cells differentiate in the thymus.^[6][10]

Development and cytolytic activation are independent of live micro-organisms but they become cytolytic in response to the exogenous antigenic substances other than live micro-organisms in the gut. IEL T cells acquire their activated memory phenotype post-thymically, in response to antigens encountered in the periphery.^[11]

Function

Their role in immune system is crucial because IELs provide a first line of defense at this extensive barrier with the outside world. All IEL T cells are antigen-experienced T cells, which typically display a cytotoxic functional phenotype. IELs mediate antigen-specific delayed-type hypersensitivity (DTH) responses, exhibit virus-specific CTL function, to express

TCRαβ⁺CD4⁺ IELs arise from conventional peripheral CD4⁺ T-cells. These cells migrate into the intestinal epithelium as effector or tissue-resident memory T cells.

In mice, up to 50% of these IELs can express CD8αα homodimer, which they acquire in the intestinal epithelium after external stimuli such as TGF-β, IFN-γ, IL-27 and retinoic acid. Function of TCRαβ⁺ CD4⁺ CD8αα⁺ IELs is unclear. Even though they express granzymes and have cytolytic properties, it has been suggested that they can also have regulatory properties in the context of chronic intestinal inflammation.^[3][17]

TCRαβ⁺CD8αβ⁺ IELs

These IELs emerge from peripherally activated conventional CD8⁺ T-cells and home to the intestinal epithelium, where they function as effector or memory cells. They continuously express

Some of these cells also express CD8αα homodimer and can be pathogenic during coeliac disease in humans.^[3]

Double positive (DP) TCRαβ⁺CD4⁺CD8αα⁺ IELs

These DP IELs are subset of induced IELs, which are CD4⁺ IELs with some functions of CD8⁺ IELs and under physiological condition their number in the intestine is very small. During the intestinal inflammation, levels of DP IELs significantly increase.^[18]

DP IELs develop independently of the

The function of CD4CD8aa IELs is due to their CD8 phenotype and granzyme B expression to prevent pathogens from invading and to maintain integrity of the intestinal epithelial barrier. Their CD4 phenotype is responsible for IL-10 and TGF-β secretion that prevents Th1-induced inflammation in the intestine, therefore their role can be complementary to T regulatory cells.^[18][22]

DP IELs probably play role in intestinal homeostasis because of their immunosuppressive function. But for their cytotoxic responses they may play an important role in the pathological process of IBD.^[18]

Natural TCR⁺ IELs

Also termed unconventional IELs, express either TCRαβ or TCRγδ and do not express either CD4 or CD8αβ, but express CD8αα homodimers. In contrast to induced TCR⁺ IELs lack expression of CD2, CD5, CD28, LFA-1, and Thy1.^[4]

TCRαβ⁺ IELs

In mice, these IELs are the most abundant at birth and with age their numbers decrease. In humans, these cells are present during gestation but are very rare in adulthood. TCRαβ⁺ IELs develop in thymus where they undergo agonist positive selection and thereby are self-reactive. Nevertheless, they have regulatory properties and protect against colitis in animal experiments. These cells are influenced by normal intestinal microbiota and vitamin D. NOD2 receptor expressed by antigen presenting cells and epithelial cells in the intestine recognizes microbes and triggers the production of IL-15 cytokine, which promotes TCRαβ⁺CD8αα⁺ IELs.^[3]

TCRγδ⁺ IELs

TCRγδ⁺ IELs develop outside of thymus and their maintenance and function in the intestinal epithelium is influenced by a cross-talk with enterocytes. Moreover, they can migrate through the epithelium with the help of interactions with epithelial cells.^[23] Most of these cells express Vγ7 in mice and Vγ4 in humans. Their function resides in the protection of the intestinal barrier against pathogens early in the infection and later they quench the inflammation and protect the barrier from tissue damage. The mechanism is not clear, but TCRγδ⁺ IELs have cytotoxic properties and can produce cytokines TGF-β, TNF-α, IFN-γ, IL-13 and IL-10 and antimicrobial peptides, all of which can contribute to the diverse functions.^[3]

Similar functions have been found in the context of colitis, where these cells seem to have pathogenic role at the beginning, whereas later they protect the epithelium against tissue damage.^[17]

TCR⁻ IELs

IELs that do not express TCR.

ILC-like IELs

These cells show properties of NK cells. In humans, they are elevated during Crohn´s disease and in mice, they are pathogenic during colitis.^[4]

iCD8α

These innate lymphocytes express homodimer CD8αα and CD3 and develop outside of thymus. They have cytotoxic and phagocytic properties, express MHC II and thereby can present antigens to conventional CD4⁺ T-cells. iCD8α protect against bacterial infections and promotes experimental colitis.^[3]

TCR⁻iCD3⁺CD8αα⁻ IELs

These cells are very similar to iCD8α population and it is unclear if this is a different subset of cells or only precursors of iCD8α.^[3]

See also

IEL of the GI tract

References