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Naive and Innate Memory Phenotype CD4⁺ T Cells Have Different Requirements for Active Itk for Their Development¹

Jianfang Hu^*, and Avery August^2,*

^* Center for Molecular Immunology and Infectious Disease and Department of Veterinary & Biomedical Sciences, and Immunology and Infectious Disease Graduate Program, The Pennsylvania State University, University Park, PA 16802

The Tec family kinase Itk regulates the development of conventional and innate CD8⁺ T cells. However, little is known about the role of Itk in the development of CD4⁺ T cell lineages, although the role of Itk in the T cell activation and function is well defined. We show in this study that Itk null mice have increased percentage of CD62L^lowCD44^high memory phenotype CD4⁺ T cells compared with wild-type mice. These cells arise directly in the thymus, express high levels of transcripts for the T-bet and IFN- and are able to produce IFN- directly ex vivo in response to stimulation. Itk deficiency greatly decreases the number of CD4⁺ T cells with CD62L^highCD44^low naive phenotype, but has no effect on the number of memory phenotype CD4⁺ T cells, indicating that the development of memory phenotype CD4⁺ T cells is Itk-independent. We further show that the development of the naive phenotype CD4⁺ T cells is dependent on active Itk signals and can be rescued by expression of Itk specifically in T cells. Our data also show that Itk is required for functional TCR signaling in these cells, but not for the innate function in response to IL-12/IL-18 or Listeria monocytogenes stimulation. These results indicate that CD62L^highCD44^low "naive" CD4⁺ and CD62L^lowCD44^high "innate memory phenotype" CD4⁺ T cells may be independent populations that differ in their requirement for Itk signals for development. Our data also suggest that CD4⁺CD62L^lowCD44^high memory phenotype T cells have innate immune function.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants AI051626 and AI065566 from the National Institutes of Health (to A.A.). J.H. is a Graduate Fellow of the Huck Institute for Life Sciences. Work at the Center for Molecular Immunology and Infectious Disease is supported in part under a grant from the Pennsylvania Department of Health.

² Address correspondence and reprint requests to Dr. Avery August, Center for Molecular Immunology and Infectious Disease, Department of Veterinary and Biomedical Sciences, 115 Henning Building, The Pennsylvania State University, University Park, PA 16802. E-mail address: axa45{at}psu.edu

³ Abbreviations used in this paper: SP, single positive; MP, memory phenotype; NP, naive phenotype; WT, wild type; CD62L, CD62 ligand.

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