TY - JOUR
T1 - CD8 expression up to the double-positive CD3low/intermediate stage of thymic differentiation is sufficient for development of peripheral functional cytotoxic T lymphocytes
AU - Zhang, X. L.
AU - Zhao, S.
AU - Borenstein, S. H.
AU - Liu, Y.
AU - Jayabalasingham, B.
AU - Chamberlain, J. W.
PY - 2001/9/3
Y1 - 2001/9/3
N2 - Control of CD8α transcription during development of α/β T cell receptor (TCR) T lymphocytes is mediated by at least two distinct stage-specific cis-acting transcriptional mechanisms (i.e., enhancers). On the CD8α-/-knockout (KO) background, cis-mechanism I and cismechanism II together mediate appropriate stage- and sublineage-specific transgenic (Tg) CD8α expression and "rescue" development of peripheral CD8+ single-positive (SP) cytotoxic T lymphocytes (CTLs). In contrast, on the wild-type (WT)/CD8+/+ or CD8α-/-KO backgrounds, a CD8α Tg directed by cis-mechanism I alone is activated during the double negative [DN] to double positive [DP] transition and expressed up to the CD3low/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 CD8α transcription. To examine this issue, phenotypic and functional studies were performed for thymocytes and T cells of CD8α-/-KO mice that expressed a CD8α Tg under control of cis-mechanism I only. Despite loss of CD8α expression at the DP CD3low/intermediate stage, increased populations of mature CD3hiCD4-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 CD8α transcription. Further, CD8 expression beyond the CD3low/intermediate DP thymic stage is not essential for CTL development in vivo or function.
AB - Control of CD8α transcription during development of α/β T cell receptor (TCR) T lymphocytes is mediated by at least two distinct stage-specific cis-acting transcriptional mechanisms (i.e., enhancers). On the CD8α-/-knockout (KO) background, cis-mechanism I and cismechanism II together mediate appropriate stage- and sublineage-specific transgenic (Tg) CD8α expression and "rescue" development of peripheral CD8+ single-positive (SP) cytotoxic T lymphocytes (CTLs). In contrast, on the wild-type (WT)/CD8+/+ or CD8α-/-KO backgrounds, a CD8α Tg directed by cis-mechanism I alone is activated during the double negative [DN] to double positive [DP] transition and expressed up to the CD3low/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 CD8α transcription. To examine this issue, phenotypic and functional studies were performed for thymocytes and T cells of CD8α-/-KO mice that expressed a CD8α Tg under control of cis-mechanism I only. Despite loss of CD8α expression at the DP CD3low/intermediate stage, increased populations of mature CD3hiCD4-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 CD8α transcription. Further, CD8 expression beyond the CD3low/intermediate DP thymic stage is not essential for CTL development in vivo or function.
KW - CD8
KW - Gene expression
KW - Stage-specific regulation
KW - Sublineage commitment
KW - Thymic selection
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U2 - 10.1084/jem.194.5.685
DO - 10.1084/jem.194.5.685
M3 - Article
C2 - 11535636
AN - SCOPUS:0035801606
SN - 0022-1007
VL - 194
SP - 685
EP - 693
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 5
ER -