Human CD4 expression at the late single-positive stage of thymic development supports T cell maturation and peripheral export in CD4-deficient mice.
Positive selection of developing thymocytes is initiated at the double-positive (DP) CD4(+)CD8(+) stage of their maturation. Accordingly, expression of a human CD4 (hCD4) transgene beginning at the DP stage has been shown to restore normal T cell development and function in CD4-deficient mice. However, it is unclear whether later onset CD4 expression would still allow such a restoration. To investigate this issue, we used transgenic mice in which a hCD4 transgene is not expressed on DP, but only on single-positive cells. By crossing these animals with CD4-deficient mice, we show that late hCD4 expression supports the maturation of T cell precursors and the peripheral export of mature TCRalphabeta(+) CD8(-) T cells. These results were confirmed in two different MHC class II-restricted TCR transgenic mice. T cells arising by this process were functional in the periphery because they responded to agonist peptide in vivo. Interestingly, thymocytes of these mice appeared refractory to peptide-induced negative selection. Together, these results indicate that the effect of CD4 on positive selection of class II-restricted T cells extends surprisingly late into the maturation process by a previously unrecognized pathway of differentiation, which might contribute to the generation of autoreactive T cells.
Boyer
Olivier
O
Laboratoire de Biologie et Thérapeutique des Pathologies Immunitaires and Centre National de la Recherche Scientifique Unité Mixte de Recherche 7087, Hôpital Pitié-Salpêtrière, 83 boulevard de l'hôpital, F-75013 Paris, France.
Marodon
Gilles
G
Cohen
José L
JL
Lejeune
Laurence
L
Irinopoulou
Théano
T
Liblau
Roland
R
Bruneval
Patrick
P
Klatzmann
David
D
D000595:Amino Acid Sequence; D000818:Animals; D015704:CD4 Antigens / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D017637:Clonal Deletion / Q000235:genetics; D003433:Crosses, Genetic; D003574:Cytochrome c Group / Q000008:administration & dosage / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D007275:Injections, Intravenous; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D010455:Peptides / Q000008:administration & dosage / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis; D013234:Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D019076:Transgenes / Q000276:immunology*
D015704:CD4 Antigens; D003574:Cytochrome c Group; D000949:Histocompatibility Antigens Class II; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta