Altered Development of CD8+ T Cell Lineages in Mice Deficient for the Tec Kinases Itk and Rlk

Abstract

Mutations affecting the Tec kinases Itk and Rlk decrease T cell receptor-induced Ca2+ 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-γ, 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. © 2006 Elsevier Inc. All rights reserved.