ReviewExtrathymic pathways of T-cell differentiation and immunomodulation
Section snippets
Properties of extrathymic T cells
Although extrathymic T cells have slightly distinct properties depending on the sites, they consistently express IL-2R β-chain (IL-2Rβ) on the surface [1], [2]. Similar to the case of NK cells, extrathymic T cells have the IL-2Rα−β+ phenotype (i.e., an intermediate affinity IL-2R). In contrast, conventional T cells (i.e., thymus-derived T cells) have the IL-2Rα−β− phenotype under resting conditions but have the IL-2Rα+β+ phenotype (i.e., a high affinity IL-2R) under activated conditions. In
Relationship between extrathymic T cells and NKT cells
We first characterized extrathymic T cells as DN CD4−8− TCRint cells carrying forbidden clones, in the liver around 1990 [7], [15], [16]. In earlier and subsequent studies [17], [18], [19], T cells with a NK marker, NK1.1, were identified in the thymus, although they are an extremely minor population. Attention has been focused on these T cells, because they carry many properties distinct from conventional T cells which are generated in the mainstream of the thymus. They are CD4+ or DN CD4−8−.
Why the liver and intestine are the major sites for extrathytmic T cell differentiation
Extrathymic T cells are abundant in the liver and intestine [8], [9]. Since the liver phylogenetically developed from the intestine as an exocrine gland to excrete bile, it and the intestine share similar properties, namely, the continuous renewal of epithelia (hepatocytes themselves in the liver) and the presence of extrathymic T cells. The emergence of living beings onto land made possible by the development of pulmonary respiration which occurred 360 million years ago [30]. Until that time,
Elements supportive of extrathymic T-cell differentiation
We have previously reported that c-kit+ stem cells exist even in the adult liver [33]. These c-kit+ cells isolated from the liver have potential as pluripotent stem cells; namely, they give rise to erythroid cells in the bone marrow, extrathymic T cells (and granulocytes) in the liver, and conventional T cells in the thymus when transferred into lethally irradiated mice.
When mice are administered with estrogen, many clusters of lymphoid cells appear in the parenchymal space of the liver. c-kit+
Autoreactivity of extrathymic T cells
In the case of mice, forbidden clones can be identified by the Mls system. Thus, superantigens which are the products of retrovirus infected in mice, are recognized by some specific Vβ+ cells. By using this system, we have demonstrated that forbidden clones are confined to IL-2Rβ+ TCRint cells, but are not found in IL-2Rβ− TCRhigh cells at all [31]. In other words, conventional T cells which are generated through the mainstream of T-cell differentiation in the thymus, do not contain forbidden
Aging
Extrathymic T cells including NKT cells are very few in number in youth, even in the liver, and expand with aging. In other words, extrathymic T cells tend to expand in parallel with thymic involution. In the case of mice, IL-2Rβ+ TCRint cells become detectable at the age of 4 weeks in the liver [2], [8], [9]. This is also true of NKT cells [42], [43]. Up to the age of 1.5 years, the number and proportion of IL-2Rβ+ TCRint cells and NKT cells increase but the number and proportion of NKT cells
Human counterparts of extrathymic T cells or NKT cells
Human counterparts of extrathymic T cells have been identified as CD56+ T cells and CD57+ T cells [56], [57]. Similar to the case in mice, these T cells are estimated to be granular lymphocytes in morphology. When compared with the morphology of NK cells, these extrathymic T cells have a smaller cell size and fewer cytoplasmic granules. This morphological nature indicates that extrathymic T cells are at the intermediate position between NK cells and conventional T cells in phylogeny.
CD56+ T
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2021, Developmental and Comparative ImmunologyCitation Excerpt :Nevertheless, its possible modulation by oestrogen remains to be demonstrated. In fact, in mammals E2 has been suggested to stimulate adult intrathymic development of γδ T cells, which results in the increase of the number of γδ T cells in the peripheral organs (Abo, 2001; Chapman et al., 2015). The results of the present study also contrast with the observation made in adult sea bass, in which E2-treatment increased tcrg-expression in the spleen of males only (Paiola et al., 2018).
Oestrogen, an evolutionary conserved regulator of T cell differentiation and immune tolerance in jawed vertebrates?
2018, Developmental and Comparative ImmunologyCitation Excerpt :In the mammalian thymus, E2-exposure increased the proportion of T cells with mature phenotypes CD3, CD4 or CD8 SP. Therefore, E2 was presumed to stimulate an alternative intrathymic pathway of CD4 and CD8 double negative T cell maturation including αβ and γδ T cells (Abo, 2001; Chapman et al., 2015; Rijhsinghani et al., 1996; Screpanti et al., 1991). Except for the γδ T cells, this intrathymic pathway could not be directly evidenced for the sea bass thymus, because, although sex-depended differences existed, no treatment effect became visible.
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2009, Clinical ImmunologyCitation Excerpt :These studies showed lower numbers of CD4+ T cells [10–12] and naive T cells [9,10] in the thymectomized group. They speculated that thymectomy was incomplete [11], T cells may be generated de novo at extrathymic sites [10,29], or that recent thymic emigrants generated before thymectomy persist for decades [30,31]. Investigations in a previously thymectomized patient who was irradiated before bone marrow transplantation [32] and a thymectomized AIDS patient [30] demonstrated the thymus dependence of CD4+ naive T cell generation and the presence of a long-lived CD4+CD45RA+CD62L+TRECnegative population of T cells.