Review
Extrathymic pathways of T-cell differentiation and immunomodulation

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Abstract

It is well established that the thymus is an essential organ for the support of T-cell differentiation. However, some T cells, termed extrathymic T cells, have been found to differentiate without such support by the thymus. The major sites of these T cells are the intestine and liver. Subsequent studies have revealed that extrathymic T cells are also present in the uterus and exocrine glands (e.g., the salivary gland). Depending on the sites, extrathymic T cells have some distinct properties as well as some common properties. For example, all extrathymic T cells have a TCR-CD3 complex similar to thymus-derived T cells. Extrathymic T cells comprise both αβT cells and γδT cells. Although extrathymic T cells are very few in number at any extrathymic sites in youth, they increase in number as a function of age. This phenomenon seems to occur in parallel with thymic involution. Even in youth, extrathymic T cells are activated in number and function by stress, in autoimmune diseases, and during pregnancy. Acute thymic atrophy always accompanies this activation. Therefore, reciprocal regulation between extrathymic T cells and thymus-derived T cells might be present. We hypothesize that extrathymic T cells are intimately associated with innate immunity and that the mechanisms underlying autoimmune diseases and intracellular infection (e.g., malaria) cannot be properly understood without introducing the concept of extrathymic T cells.

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-2Rαβ+ phenotype (i.e., an intermediate affinity IL-2R). In contrast, conventional T cells (i.e., thymus-derived T cells) have the IL-2Rαβ 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 CD48 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 CD48.

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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