The thymic microenvironment differentially regulates development and trafficking of invariant NKT cell sublineages.
The regulatory role of the thymic microenvironment during trafficking and differentiation of the invariant NKT (iNKT) cell lineage remains poorly understood. In this study, we show that fractalkine receptor expression marks emigrating subpopulations of the NKT1, NKT2, and NKT17 sublineages in the thymus and peripheral organs of naive mice. Moreover, NKT1 sublineage cells can be subdivided into two subsets, namely NKT1(a) and NKT1(b), which exhibit distinct developmental and tissue-specific distribution profiles. More specifically, development and trafficking of the NKT1(a) subset are selectively dependent upon lymphotoxin (LT)α1β2-LTβ receptor-dependent differentiation of thymic stroma, whereas the NKT1(b), NKT2, and NKT17 sublineages are not. Furthermore, we identify a potential cellular source for LTα1β2 during thymic organogenesis, marked by expression of IL-7Rα, which promotes differentiation of the NKT1(a) subset in a noncell-autonomous manner. Collectively, we propose a mechanism by which thymic differentiation and retention of the NKT1 sublineage are developmentally coupled to LTα1β2-LTβ receptor-dependent thymic organogenesis.
Department of Rheumatology, Laboratory for Molecular Immunology and Inflammation, Ghent University Hospital, Ghent B-9000, Belgium; Michael.Drennan@ugent.be Dirk.Elewaut@ugent.be.
Michael B
http://orcid.org/0000-0001-9832-1707
MB
Drennan
Department of Rheumatology, Laboratory for Molecular Immunology and Inflammation, Ghent University Hospital, Ghent B-9000, Belgium;
Srinath
S
Govindarajan
Department of Rheumatology, Laboratory for Molecular Immunology and Inflammation, Ghent University Hospital, Ghent B-9000, Belgium;
Katelijne
K
De Wilde
Department of Microbiology and Immunology, University of Leuven, Leuven 3000, Belgium;
Susan M
SM
Schlenner
Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
Carl
C
Ware
Biological Faculty, Lomonosov Moscow State University, Moscow 119991, Russia; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia; and.
Sergei
S
Nedospasov
Department for Cellular Immunology, German Cancer Research Center, D-69120 Heidelberg, Germany.
Hans-Reimer
HR
Rodewald
Department of Rheumatology, Laboratory for Molecular Immunology and Inflammation, Ghent University Hospital, Ghent B-9000, Belgium; Michael.Drennan@ugent.be Dirk.Elewaut@ugent.be.
Dirk
D
Elewaut
D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002465:Cell Movement; D060833:Cellular Microenvironment; D016000:Cluster Analysis; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D016130:Immunophenotyping; D053699:Interleukin-7 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053361:Lymphotoxin alpha1, beta2 Heterotrimer / Q000378:metabolism; D053259:Lymphotoxin beta Receptor / Q000378:metabolism; D053308:Lymphotoxin-beta / Q000172:deficiency; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D055611:Natural Killer T-Cells / Q000166:cytology* / Q000378:metabolism*; D010641:Phenotype; D011247:Pregnancy; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D015728:Receptors, HIV / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000378:metabolism*; D060168:Thymocytes / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism*
D000073883:CX3C Chemokine Receptor 1; D053699:Interleukin-7 Receptor alpha Subunit; D053361:Lymphotoxin alpha1, beta2 Heterotrimer; D053259:Lymphotoxin beta Receptor; D053308:Lymphotoxin-beta; D018121:Receptors, Cytokine; D015728:Receptors, HIV