The thymus chapter in the life of gut-specific intra epithelial lymphocytes

Abstract

The intestinal intraepithelial lymphocytes (IEL) represent multi-lineage T cell populations. In addition to a major gammadeltaTCR(+) T cell subset, many IEL express alphabetaTCRs and they can be separated into alphabeta sublineages. Some TCRalphabeta(+)IEL have characteristics in common with conventional TCRalphabeta(+)T cells whereas others share an unconventional phenotype with their TCRgammadelta(+) counterparts. Because the latter are enriched for autoreactive TCRs and can be generated in the absence of a thymus, it has long been postulated that some IEL subsets develop locally in the intestine. Several new data however, indicate that under physiological conditions, IEL require a thymic education that directs lineage commitment and functional differentiation. This review will discuss the contributions of the thymus in shaping the various intestinal IEL sublineages.

Figure 1. Differentiation pathways and checkpoints of TCRαβ and TcRγδ T cells

DN thymocytes are subdivided in 4 populations (DN1 to DN4) that contain precursors belonging to the αβ- and γδ-lineage. DN TcRγδ precursors transition through agonist TCRγδ selection and give rise to waves of TCRγδ subsets with different homing capacity. Agonist selected TCRγδ IEL precursors migrate to the gut epithelium independently of functional S1P1. At the DN3 stage, precursors that successfully rearranged the β-chain will undergo pre-TCR driven β-selection and transition to the DP (CD4⁺CD8αβ⁺) or TP (CD4⁺CD8αβ⁺CD8αα⁺) stage. The DP population contains αβ lineage committed precursors that will undergo positive and negative conventional selection and commit to the CD4- or CD8αβ-SP sublineage. Positive selected SP thymocytes egress the thymus in a S1P1-dependent fashion and reside in the periphery as naïve T cells. Antigenic stimulation further differentiate these cells to effector cells that gain the capacity to migrate to the intestinal epithelium. TP thymocytes can proceed through agonist selection and give rise to mature DN TCRαβ thymocytes that home to the intestinal epithelium in a S1P1-independent way. Molecules that have important roles during T cell differentiation were added. Solid black arrows show established pathways whereas dashed arrows indicate uncertain transitions.