This article is a US Government work and is in the public domain in the USA • Immunological Reviews 228/2009 93 Julie A. Readinger Kristen L. Mueller Ana M. Venegas Reiko Horai Pamela L. Schwartzberg Tec kinases regulate T-lymphocyte development and function: new insights into the roles of Itk and Rlk / Txk Authors’ address Julie A. Readinger 1 , Kristen L. Mueller 1 , Ana M. Venegas 1 , Reiko Horai 1 , Pamela L. Schwartzberg 1 1 National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA Correspondence to: Pamela L. Schwartzberg National Institutes of Health–sNational Human Genome Research Institute Building 49, Room 4A38 49 Convent Dr., MSC 4472 Bethesda, MD 20892, USA Tel.: +1 301 435 1906 Fax: +1 301 402 2170 e-mail: pams@nhgri.nih.gov Immunological Reviews 2009 Vol. 228: 93–114 Printed in Singapore. All rights reserved This article is a US Government work and is in the public domain in the USA Immunological Reviews 0105-2896 Summary: The Tec (tyrosine kinase expressed in hepatocellular carci- noma) family of non-receptor tyrosine kinases consists of five members: Tec, Bruton’s tyrosine kinase (Btk), inducible T-cell kinase (Itk), resting lymphocyte kinase (Rlk / Txk), and bone marrow-expressed kinase (Bmx / Etk). Although their functions are probably best understood in antigen receptor signaling, where they participate in the phosphorylation and regulation of phospholipase C-c (PLC-c), it is now appreciated that these kinases contribute to signaling from many receptors and that they participate in multiple downstream pathways, including regulation of the actin cytoskeleton. In T cells, three Tec kinases are expressed, Itk, Rlk / Txk, and Tec. Itk is expressed at highest amounts and plays the major role in regulating signaling from the T-cell receptor. Recent studies provide evidence that these kinases contribute to multiple aspects of T-cell biology and have unique roles in T-cell development that have revealed new insight into the regulation of conventional and innate T-cell development. We review new findings on the Tec kinases with a focus on their roles in T-cell development and mature T-cell differentiation. Keywords: T cells, Th1 / Th2 / Th17 cells, asthma, thymus, protein kinases / phosphatases Introduction Approximately 15 years ago, two groups discovered that mutations of a novel non-receptor tyrosine kinase, now termed Bruton’s tyrosine kinase (Btk), were the cause of a severe immunodeficiency X-linked agammaglobulinemia (XLA), which is characterized by impaired B-cell develop- ment, low to absent serum immunoglobulins (Igs), and recurrent infections (1, 2). It was recognized at that time that Btk was most homologous to two other previously cloned kin- ases, Tec (tyrosine kinase expressed in hepatocellular carci- noma) and inducible T-cell kinase / expressed mainly in T cells (Itk / Emt) (3). The Tec family of kinases now consists of five related members: Btk, Tec, Itk, resting lymphocyte kinase (Rlk), also known as Txk, and bone marrow-expressed kinase (Bmx / Etk), most of which are expressed primarily in a variety