Altered development of CD8+ T cell lineages in mice deficient for the Tec kinases Itk and Rlk.
Mutations affecting the Tec kinases Itk and Rlk decrease T cell receptor-induced Ca(2+) mobilization and Erk kinase activation and impair both positive and negative thymic selection. Itk(-/-) and Rlk(-/-)Itk(-/-) mice also have decreased CD4:8 T cell ratios, suggestive of altered CD4:8 lineage commitment. Nonetheless, we find that CD8 single-positive (SP) thymocytes and peripheral CD8(+) T cells in these mice do not resemble conventional CD8(+) T cells. Instead, these cells express memory markers, rapidly produce interferon-gamma, and can be selected on hematopoietically derived cells, similar to MHC class Ib-restricted "innate-type" lymphocytes. Itk deficiency also greatly increases the number of cells selected by MHC class Ib. Expression of a hypersensitive Erk2 mutant partially corrects the CD8(+) T cell phenotypes in Itk(-/-) mice, arguing that altered signaling permits development of this innate-type CD8(+) cell population. Our results suggest that Tec kinases differentially regulate development of conventional versus nonconventional lymphocytes.
Broussard
Christine
C
National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Fleischacker
Christine
C
Fleischecker
Christine
C
Horai
Reiko
R
Chetana
Madeva
M
Venegas
Ana M
AM
Sharp
Leslie L
LL
Hedrick
Stephen M
SM
Fowlkes
B J
BJ
Schwartzberg
Pamela L
PL
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology; D002454:Cell Differentiation; D019070:Cell Lineage; D006649:Histocompatibility Antigens / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D010641:Phenotype; D011505:Protein-Tyrosine Kinases / Q000145:classification / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
D006649:Histocompatibility Antigens; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase