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In mice, villi of the small intestinal epithelium (SI-Ep) harbors 50 millions T cells, named in-traepithelial lymphocytes (IELs), representing up to half the number of T cells in the organism (Rocha et al., 1991). IELs are composed of con-ventional TCR cells expressing the CD4 or the heterodimer CD8 co-receptors, and unconventional (unc) TCR cells (so-called CD8, type b or natural IELs) and TCR cells lacking CD4/CD8 co-receptors (Cheroutre et al., 2011). Many IELs are highly cytotoxic (Goodman and Lefrancois, 1989; Guy-Grand et al., 1996; Müller et al., 2000), and are charac-terized morphologically by cytoplasmic granules with high Granzyme B content (Guy-Grand et al., 1991). Full IEL development requires microbe-promoted stimulations (Guy-Grand et al., 1978; Bandeira et al., 1990). In normal euthymic mice, IEL precursors are of thymic origin (Guy-Grand et al., 2003; Cheroutre et al., 2011). Migration to the SI de-pends on the integrin 47 (Wagner et al., 1996; Lefrançois et al., 1999) whose ligand MadCAM-1 is expressed by the venules of the lamina pro-pria (LP; Berlin et al., 1993). CCR9 and its li-gand, CCL25, expressed by the SI-Ep, play an additional role (Zabel et al., 1999), but inacti-vation of one of these molecules only results in a marked deicit of IELs (Wurbel et al., 2001, 2007). 47 and CCR9 are designated “gut-tropic ” molecules. For conventional T cells, acquisition of gut-tropic molecules appears to be largely restricted to cells activated in the gut-associated lymphoid tissue (GALT), which is composed of Peyer’s patches (PPs), mesenteric lymph nodes (MLN), and isolated lymphoid follicles from the L