CD1d-independent developmental acquisition of prompt IL-4 gene inducibility in thymus CD161(NK1)-CD44lowCD4+CD8- T cells is associated with complementarity determining region 3-diverse and biased Vbeta2/Vbeta7/Vbeta8/Valpha3.2 T cell receptor usage.
Among Ag-inexperienced naive T cells, the CD1d-restricted NKT cell that uses invariant TCR-alpha-chain is the most widely studied cell capable of prompt IL-4 inducibility. We show in this study that thymus CD161-CD44lowCD4+CD8- T cells promptly produce IL-4 upon TCR stimulation, a response that displays biased Vbeta(2/7/8) and Valpha3.2 TCR usage. The association of Vbeta family bias and IL-4 inducibility in thymus CD161-CD44lowCD4+CD8- T cells is found for B6, B10, BALB/c, CBA, B10.A(4R), and ICR mouse strains. Despite reduced IL-4 inducibility, there is a similarly biased Vbeta(2/7/8) TCR usage by IL-4 inducibility+ spleen CD161-CD44lowCD4+CD8- T cells. Removal of alpha-galacotosylceramide/CD1d-binding cells from CD161-CD44lowCD4+CD8- thymocytes does not significantly affect their IL-4 inducibility. The development of thymus CD161-CD44lowCD4+CD8- T cells endowed with IL-4 inducibility and their associated use of Vbeta(2/7/8) are beta2-microglobulin-, CD1d-, and p59fyn-independent. Thymus CD161-CD44lowCD4+CD8- T cells produce low and no IFN-gamma inducibility in response to TCR stimulation and to IL-12 + IL-18, respectively, and they express diverse complementarity determining region 3 sequences for both TCR-alpha- and -beta-chains. Taken together, these results demonstrate the existence of a NKT cell distinct, TCR-repertoire diverse naive CD4+ T cell subset capable of prompt IL-4 inducibility. This subset has the potential to participate in immune response to a relatively large number of Ags. The more prevalent nature of this unique T cell subset in the thymus than the periphery implies roles it might play in intrathymic T cell development and may provide a framework upon which mechanisms of developmentally regulated IL-4 gene inducibility can be studied.
Chen
Yi-Ting
YT
Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Kung
John T
JT
D000595:Amino Acid Sequence; D000818:Animals; D018949:Antigens, CD1 / Q000378:metabolism*; D055610:Antigens, CD1d; D000954:Antigens, Surface / Q000378:metabolism; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation; D022801:Complementarity Determining Regions; D004247:DNA / Q000235:genetics; D005699:Galactosylceramides / Q000276:immunology / Q000494:pharmacology; D005786:Gene Expression Regulation; D015847:Interleukin-4 / Q000235:genetics*; D007378:Interleukins / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D037181:Lectins, C-Type / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D055651:NK Cell Lectin-Like Receptor Subfamily B; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000276:immunology*
D018949:Antigens, CD1; D055610:Antigens, CD1d; D000954:Antigens, Surface; D022801:Complementarity Determining Regions; D005699:Galactosylceramides; D007378:Interleukins; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta; C493154:alpha-galactosylceramide; D015847:Interleukin-4; D004247:DNA