Restricted TCR-alpha CDR3 diversity disadvantages natural regulatory T cell development in the B6.2.16 beta-chain transgenic mouse.
To date, analysis of mice expressing TCR-beta transgenes derived from CD4(+) T cell clones has demonstrated equivalent or higher TCR diversity in naturally occurring regulatory CD4(+) T cells (Tregs) versus conventional CD4(+) T cells (Tcons). However, TCR-alpha-chain diversity in these mice may be influenced by the inherent bias toward the CD4(+) lineage in the selected repertoires. We wished to determine whether the choice of TCR-beta-chain influences the relative diversity of the Treg and Tcon repertoires, examining as a model the B6.2.16beta-transgenic mouse, in which the fixed beta-chain is derived from a CD8(+) T cell clone. B6.2.16beta Treg thymocytes showed significantly lower TRAV17 (AV9) CDR3 sequence diversity than both syngeneic Tcon thymocytes, and Treg and Tcon thymocytes from wild-type C57BL/6 (B6) mice. The ratio of single-positive CD4(+)/single-positive CD8(+) thymocytes in B6.2.16beta mice was similar to that in B6, yet both the proportional frequency and absolute number of CD4(+)Foxp3(+) cells was significantly lower in the thymi and peripheral lymph nodes of B6.2.16beta mice. Furthermore, B6 + B6.2.16beta-->B6 mixed bone marrow chimeras revealed that the transgenic beta-chain disadvantaged Treg development in a competitive environment. These data underline the importance of the beta-chain in assessments of Treg alpha-chain diversity and provide further support for the notion that interclonal competition for entry into the Treg lineage is a significant factor in determining the composition of this lineage.
Singh
Yogesh
Y
Regulatory T Cell Laboratory, Infection and Immunity Research Group, Department of Veterinary Clinical Sciences, Royal Veterinary College, London, United Kingdom.
Ferreira
Cristina
C
Chan
Andrew C Y
AC
Dyson
Julian
J
Garden
Oliver A
OA
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015704:CD4 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002999:Clone Cells; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006131:Growth Inhibitors / Q000737:chemistry / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D015704:CD4 Antigens; D022801:Complementarity Determining Regions; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006131:Growth Inhibitors; D000949:Histocompatibility Antigens Class II; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011993:Recombinant Fusion Proteins