CD8 expression up to the double-positive CD3(low/intermediate) stage of thymic differentiation is sufficient for development of peripheral functional cytotoxic T lymphocytes.
Control of CD8alpha transcription during development of alpha/beta T cell receptor (TCR) T lymphocytes is mediated by at least two distinct stage-specific cis-acting transcriptional mechanisms (i.e., enhancers). On the CD8alpha(-/-) knockout (KO) background, cis-mechanism I and cis-mechanism II together mediate appropriate stage- and sublineage-specific transgenic (Tg) CD8alpha expression and "rescue" development of peripheral CD8(+) single-positive (SP) cytotoxic T lymphocytes (CTLs). In contrast, on the wild-type (WT)/CD8(+/+) or CD8alpha(-/-)KO backgrounds, a CD8alpha Tg directed by cis-mechanism I alone is activated during the double negative [DN] to double positive [DP] transition and expressed up to the CD3(low/intermediate) DP stage but not in more mature DP or SP thymocytes or peripheral T cells. As loss of cis mechanism I activity occurs around the onset of positive selection, it is possible that events associated with TCR/major histocompatibility complex (MHC) interactions and selection are involved in initiating these changes in CD8alpha transcription. To examine this issue, phenotypic and functional studies were performed for thymocytes and T cells of CD8alpha(-/-) KO mice that expressed a CD8alpha Tg under control of cis-mechanism I only. Despite loss of CD8alpha expression at the DP CD3(low/intermediate) stage, increased populations of mature CD3(hi)CD4(-)CD8(-) thymocytes and CD3(+)CD4(-)CD8(-) peripheral T cells were detected. By several criteria, including MHC class I-restricted antigen recognition, these cells have at least partially undergone positive and negative selection. Therefore, initiation of selection and sublineage commitment are determined before loss of cis-mechanism I-mediated control of CD8alpha transcription. Further, CD8 expression beyond the CD3(low/intermediate) DP thymic stage is not essential for CTL development in vivo or function.
Zhang
X L
XL
Research Institute, Program in Infection, Immunity, Injury and Repair, The Hospital for Sick Children, Torornto, Canada.
Zhao
S
S
Borenstein
S H
SH
Liu
Y
Y
Jayabalasingham
B
B
Chamberlain
J W
JW
D000818:Animals; D000950:Antigens, Ly / Q000276:immunology; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D016038:Skin Transplantation / Q000276:immunology / Q000473:pathology; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000254:growth & development / Q000276:immunology*; D014158:Transcription, Genetic
D000950:Antigens, Ly; D016827:CD8 Antigens; D016693:Receptors, Antigen, T-Cell, alpha-beta