CD4CD8αα IELs: They Have Something to Say

Abstract

The intraepithelial lymphocytes (IELs) that reside within the epithelium of the intestine play a critical role in maintaining the immune balance of the gut. CD4CD8αα IELs are one of the most important types of IELs, and they play an irreplaceable role in maintaining the balance of the intestinal immune system. CD4CD8αα IELs are often regarded as a special subtype of CD4+ IELs that can express CD8αα on their cytomembrane. Hence, CD4CD8αα IELs not only have the ability to modulate the functions of immune cells but also are regarded as cytotoxic T lymphocytes (CTLs). Transcription factors, microbes, and dietary factors have a substantial effect on the development of CD4CD8αα IELs, which make them exert immunosuppression and cytotoxicity activities. In addition, there is an intimate relationship between CD4CD8αα IELs and inflammatory bowel disease (IBD), whereas it is still unclear how CD4CD8αα IELs influence IBD. As such, this review will focus on the unparalleled differentiation of CD4CD8αα IELs and discuss how these cells might be devoted to tolerance and immunopathological responses in the intestinal tract. In addition, the role of CD4CD8αα IELs in IBD would also be discussed.

Intestinal intraepithelial lymphocytes: Maintainers of intestinal immune tolerance and regulators of intestinal immunity

“…Without the VDR, CD4 + T cells cannot acquire the expression of CD8αα and fail to home to the gastrointestinal tract, which contributes to the normal bacterial flora becoming unbalanced 23 . The intestinal development of CD4 + CD8αα + IELs has been described previously 68 . Similar to CD8αα + TCRαβ + IELs, the TCR repertoire of CD4 + TCRαβ + IELs is highly oligoclonal in mature mice and adults, which might be a result of intestinal factor selection, such as microbial colonization 69,70 …”

“…23 The intestinal development of CD4 + CD8 + IELs has been described previously. 68 Similar to CD8 + TCR + IELs, the TCR repertoire of CD4 + TCR + IELs is highly oligoclonal in mature mice and adults, which might be a result of intestinal factor selection, such as microbial colonization. 69,70 Generally, consistent with Th features, CD4 + TCR + IELs play an indispensable role in protective immunity in the intestinal mucosa.…”

Coix Seed Diet Ameliorates Immune Function Disorders in Experimental Colitis Mice

“…In our experiment, DSS attack dramatically decreased CD8 + T cells in colon mucosa, consistent with a clinical study [ 16 ]; however, the CSF upregulated CD8 + T cells in the experimental colitis mice, indicating a higher eliminating potential of the tissue. Recently, CD4 + CD8 + DP T-lymphocytes have been found beneficial in the immune response of UC [ 17 ]. These lymphocytes are differentiated from CD4 + T lymphocytes and can maintain barrier integrity and eliminate damaged cells [ 18 ].…”

Exposures to uranium and arsenic alter intraepithelial and innate immune cells in the small intestine of male and female mice

“…Intriguingly, the major differences between female and male mice identified in this study were to immune subsets that have known roles in autoimmunity and inflammatory conditions. The reduction of CD4 + IELs, which have known regulatory functions in suppressing inflammatory immune responses (Groux et al, 1997;Reis et al, 2013;Costes et al, 2019;Zhou et al, 2019), combined with the imbalance of immature/ proinflammatory and mature macrophages among females exposed to environmentally relevant levels of As 3+ may be creating conditions that increase susceptibility to inflammatory and autoimmune conditions.…”

“…Natural IELs initiate from T cell differentiation in the thymus, where they mature to the triple negative stage (CD3ε − , CD4 − , and CD8αβ − ), prior to entering an alternative differentiation pathway and homing to the gut where they give rise to CD3ε + , CD4 − , TCRαβ + , CD8αα +/− or CD3ε + , CD4 − , TCRγδ + , CD8αα +/− IEL subsets (Lambolez et al, 2002;Lambolez et al, 2006;Cheroutre and Lambolez, 2008;Cheroutre et al, 2011;Peaudecerf et al, 2011). In contrast, induced IEL subsets are antigen experienced T cells that differentiate to mature CD4 + or CD8αβ + stages in the thymus prior to migration to the gut (Cheroutre and Lambolez, 2008;Cheroutre et al, 2011;Olivares-Villagomez and Van Kaer, 2018;Zhou et al, 2019). Regardless of origin and location of differentiation, IELs represent critical immune cells that have diverse functions ranging from regulatory, helper-like activities to effector and cytotoxic properties (Cheroutre et al, 2011;Olivares-Villagomez and Van Kaer, 2018).…”