{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T15:17:41Z","timestamp":1779376661147,"version":"3.53.1"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T00:00:00Z","timestamp":1693958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Intraepithelial lymphocytes (IELs) are the first immune cells to contact and fight intestinal pathogens such as <jats:italic>Cryptosporidium<\/jats:italic>, a widespread parasite which infects the gut epithelium. IFN-\u03b3 producing CD4<jats:sup>+<\/jats:sup> T IELs provide an efficient and a long-term protection against cryptosporidiosis while intraepithelial type 1 innate lymphoid cells limits pathogen spreading during early stages of infection in immunodeficient individuals. Yet, the role of T-cell like innate IELs, the most frequent subset of innate lymphocytes in the gut, remains unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To better define functions of innate IELs in cryptosporidiosis, we developed a co-culture model with innate IELs isolated from <jats:italic>Rag2<jats:sup>-\/-<\/jats:sup><\/jats:italic> mice and 3D intestinal organoids infected with <jats:italic>C. parvum<\/jats:italic> using microinjection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Thanks to this original model, we demonstrated that innate IELs control parasite proliferation. We further showed that although innate IELs secrete IFN-\u03b3 in response to <jats:italic>C. parvum<\/jats:italic>, the cytokine was not sufficient to inhibit parasite proliferation at early stages of the infection. The rapid protective effect of innate IELs was in fact mediated by a cytotoxic, granzyme-dependent mechanism. Moreover, transcriptomic analysis of the Cryptosporidium-infected organoids revealed that epithelial cells down regulated Serpinb9b, a granzyme inhibitor, which may increase their sensitivity to cytolytic attack by innate IELs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Based on these data we conclude that innate IELs, most likely T-cell-like innate IELs, provide a rapid protection against <jats:italic>C. parvum<\/jats:italic> infection through a perforin\/granzymes-dependent mechanism. <jats:italic>C. parvum<\/jats:italic> infection. The infection may also increase the sensitivity of intestinal epithelial cells to the innate IEL-mediated cytotoxic attack by decreasing the expression of Serpin genes.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1229406","type":"journal-article","created":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T18:12:05Z","timestamp":1694023925000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Cytotoxic innate intraepithelial lymphocytes control early stages of Cryptosporidium infection"],"prefix":"10.3389","volume":"14","author":[{"given":"Fatima","family":"Hariss","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Delbeke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karine","family":"Guyot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauline","family":"Zarnitzky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad","family":"Ezzedine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Certad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertrand","family":"Meresse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,9,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-018-0013-7","article-title":"Diverse developmental pathways of intestinal intraepithelial lymphocytes","volume":"18","author":"McDonald","year":"2018","journal-title":"Nat Rev Immunol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1615\/CritRevImmunol.2021039957","article-title":"Unconventional intestinal intraepithelial lymphocytes in health and disease","volume":"41","author":"Nazmi","year":"2021","journal-title":"Crit Rev Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.02.010","article-title":"Intraepithelial type 1 innate lymphoid cells are a unique subset of cytokine responsive interferon-\u03b3-producing cells","volume":"38","author":"Fuchs","year":"2013","journal-title":"Immunity"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.07.018","article-title":"Interleukin-15-dependent T-cell-like innate intraepithelial lymphocytes develop in the intestine and transform into lymphomas in celiac disease","volume":"45","author":"Ettersperger","year":"2016","journal-title":"Immunity"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.08.010","article-title":"CD8\u03b1\u03b1 + Innate-type lymphocytes in the intestinal epithelium mediate mucosal immunity","volume":"41","author":"Van Kaer","year":"2014","journal-title":"Immunity"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0215883","article-title":"Innate CD8\u03b1\u03b1+ cells promote ILC1-like intraepithelial lymphocyte homeostasis and intestinal inflammation","volume":"14","author":"Nazmi","year":"2019","journal-title":"PloS One"},{"key":"B7","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1128\/iai.64.7.2556-2562.1996","article-title":"Immunity to Cryptosporidium muris Infection in Mice Is Expressed through Gut CD4\u03e9 Intraepithelial Lymphocytes","volume":"64","author":"Mcdonald","year":"1996","journal-title":"Infect Immun"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1097\/00000441-200011000-00002","article-title":"Adoptive transfer of immunity with intraepithelial lymphocytes in Cryptosporidium parvum-infected severe combined immunodeficient mice","volume":"320","author":"Adjei","year":"2000","journal-title":"Am J Med Sci"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.65.8.3074-3079.1997","article-title":"Gut intraepithelial lymphocytes induce immunity against Cryptosporidium infection through a mechanism involving gamma interferon production","volume":"65","author":"Culshaw","year":"1997","journal-title":"Infect Immun"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1128\/iai.60.8.3325-3331.1992","article-title":"Immune responses to Cryptosporidium muris and Cryptosporidium parvum in adult immunocompetent or immunocompromised (nude and SCID) mice","volume":"60","author":"McDonald","year":"1992","journal-title":"Infect Immun"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.147.3.1014","article-title":"Cryptosporidium infection in an adult mouse model. 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