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T cells are characterized by their ability to ex-pand dramatically in an antigen-specific manner during an immune challenge. After an initial im-mune response, a small proportion of respond-ing T cells survive and give rise to memory cells (Bruno et al., 1996). Memory T cells express ele-vated levels of CD44 and can be divided fur-ther into central-memory (CD62Lhi CCR7hi) and effector-memory (CD62Llo CCR7lo) com-partments. However, not all T cells that display the phenotype of memory cells are the product of a classical antigen-specific immune response (Sprent and Surh, 2011). For example, such cells are found in unimmunized mice, including those raised in germ-free and antigen-free conditions (Dobber et al., 1992; Vos et al., 1992). The pre-cise ontogeny of such cells remains elusive, although several mechanisms by which naive cells can adopt a memory phenotype have been characterized. Naive T cells introduced into lymphopenic environments adopt a memory phenotype through a process of homeostatic proliferation in response to IL-7 and MHC (Goldrath et al., 2000; Murali-Krishna and Ahmed, 2000). Additionally, increased produc-tion of IL-4 has been linked to the development of memory phenotype–innate T cell populations in studies of several knockout mouse models (Lee et al., 2011). The T cell response is tightly regulated by the balance of phosphorylation and dephos-phorylation of intracellular signaling molecules. Shp1 (encoded by Ptpn6) is a protein tyrosine phosphatase expressed ubiquitously in hemato-poietic cells and has been broadly characterized as a negative regulator of immune cell activation (Pao et al., 2007a; Lorenz, 2009). The physio-logical relevance of Shp1 as a key negative reg-ulator of the immune response is illustrated b