CD45 can act as a negative regulator for the transition from early to late CD4+ CD8+ thymocytes.
The differentiation process from CD4-CD8- double-negative (DN) thymocytes to CD4+CD8+ double-positive (DP) stage is accompanied by vigorous proliferation. The resulting DP cells contain a sizable proportion of large cycling cells, but most DP cells are small resting cells. To explore the molecular mechanisms which regulate cell proliferation of DP thymocytes prior to further development, we used TCR-transgenic (Tg) mice with non-selecting MHC (Tg-Neut), which contain almost exclusively DP thymocytes that are not subject to either positive or negative selection. In Tg-Neut, the thymus contained DP cells of relatively large size, which showed higher extracellular signal-regulated kinase activity and enhanced responsiveness to mitogen compared to small DP cells. This indicates that all the large DP cells in the thymus are not positively selected and that they possess proliferative potential. When Tg-Neut mice were backcrossed with CD45 knockout mice (CD454-/- Tg-Neut), the thymus showed an increase of large DP cells and cycling cells, but a decrease of apoptotic cells. Furthermore, Bcl-2 expression and Jun N-terminal kinase activity, which are associated with resistance to apoptosis, were enhanced. These observations suggest that thymocyte proliferation in the DP stage is suppressed by a CD45-related process with regulation of mitogen-activated protein kinase and Bcl-2 unless DP cells receive TCR-mediated signals.
Department of Immunology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
T
T
Sato
S
S
Nunomura
C
C
Sato
K
K
Hozumi
Y
Y
Kumagai
T
T
Nishimura
T W
TW
Mak
K
K
Kishihara
S
S
Habu
D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000032:analysis; D002454:Cell Differentiation; D002455:Cell Division; D048429:Cell Size; D003433:Crosses, Genetic; D017493:Leukocyte Common Antigens / Q000276:immunology*; D008285:Major Histocompatibility Complex; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000032:analysis; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D008934:Mitogens / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*
D008934:Mitogens; D011948:Receptors, Antigen, T-Cell; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D017493:Leukocyte Common Antigens