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Thymic and extrathymic T-cell development
REVIEW
Thymic and extrathymicT-cell development In recent times, a series of breakthroughs in the analysis of intrathymic events made a full understanding of T-cell development appear to be a readily achievable goal. While this may still be the case, two recent revelations introduce a note of caution. First, as described below by Benedita Rocha and colleagues, a large number of T ceils develop in the complete absence of a thymus; indeed, in some organs these thymus-independent lymphocytes comprise the majority of T cells. Second a lineage of thymus-derived T cells that does not follow the classical rules of positive and negative selection has been discovered. This population is described by Harald von Boehmer. Taken together, these findings argue that, rather than the beginning of the end, we have just reached the end of the beginning of the analysis of T-cell development.
The extrathymicT-cell development pathway Benedita Rocha, PierreVassalli and Delphine Guy-Grand In normal mice, not all T-lineage cells are generated and selected in the thymus; an alternative, extrathymic, development pathway exists. Extrathymic T cells are rare in the spleen and lymph nodes, but are abundant in some tissues, such as the gut. Here, Benedita Rocha, Pierre Vassalli and Delphine Guy-Grand discuss the rules of selection of extrathymic T cells, assess the possible role of these cells in the defence of epithelial integrity and their potential role in autoimmune disease. T-cell differentiation in the absence of a thymus was originally described in athymic (nude) mice and rats. However, the notion that T-cell receptor-positive (TCR +) lymphocytes of nude mice have an extrathymic origin was a matter of some controversy I. They were originally proposed to result from an inefficient differentiation process, taking place in abnormal thymic rudiments. Eventually, the characterization of the TCR + cells of nude mice showed that these lymphocytes differ from the TCR0q3+ cells that are the products of differentiation in the thymus, from CD4+CD8ct[3÷ (double positive) precursors into CD4+CD8ct~ - or CD4-CD80qB÷ (single positive) mature progeny. These cells can be termed 'thymus differentiated and selected' (TDS) cells. The T cells of nude mice are not the result of the usual processes of T-cell differentiation and selection: however, cells with characteristics comparable to those of nude mice do exist in normal, euthymic mice. It has recently become apparent that, although their distribution in the body is very different from that of the TDS cells, the total
number of thymus-independent cells is very high. The aim of this review is to summarize what is presently understood about this extrathymic pathway. TCR + cells in the nude mice In nude mice, lymphocytes expressing the CD3-TCR complex are present in the spleen, lymph nodes 1-8, gut 9-IT, liver 12 and skin L~. They appear relatively late in ontogeny and increase in numbers only with aging 2,4'~°. Even in aged nude mice, the total number of T cells remains lower than that found in euthymic mice. The T cells of athymic animals may express either type of TCR, oq3 or ~'8. The distribution of the two cell types varies in different organs, between species (mouse or rat) and, within the same species, between different strains. Changes in the proportions of TCRot~+ and TCR~'8+ T cells also occur with aging"4'*% In contrast to euthymic mice, in which TCRoq3+ cells predominate in the thymus, spleen and lymph nodes, TCRo~ T cells are never the predominant population in nude mice; indeed, TCR?6+ T cells constitute a majority in some
© 1992, Elsevier Science Publishers lid, tlK.
Immunology Today
449
VoL 13 No. 11 19o2
Thymic and extrathymicT-cell development In recent times, a series of breakthroughs in the analysis of intrathymic events made a full understanding of T-cell development appear to be a readily achievable goal. While this may still be the case, two recent revelations introduce a note of caution. First, as described below by Benedita Rocha and colleagues, a large number of T ceils develop in the complete absence of a thymus; indeed, in some organs these thymus-independent lymphocytes comprise the majority of T cells. Second a lineage of thymus-derived T cells that does not follow the classical rules of positive and negative selection has been discovered. This population is described by Harald von Boehmer. Taken together, these findings argue that, rather than the beginning of the end, we have just reached the end of the beginning of the analysis of T-cell development.
The extrathymicT-cell development pathway Benedita Rocha, PierreVassalli and Delphine Guy-Grand In normal mice, not all T-lineage cells are generated and selected in the thymus; an alternative, extrathymic, development pathway exists. Extrathymic T cells are rare in the spleen and lymph nodes, but are abundant in some tissues, such as the gut. Here, Benedita Rocha, Pierre Vassalli and Delphine Guy-Grand discuss the rules of selection of extrathymic T cells, assess the possible role of these cells in the defence of epithelial integrity and their potential role in autoimmune disease. T-cell differentiation in the absence of a thymus was originally described in athymic (nude) mice and rats. However, the notion that T-cell receptor-positive (TCR +) lymphocytes of nude mice have an extrathymic origin was a matter of some controversy I. They were originally proposed to result from an inefficient differentiation process, taking place in abnormal thymic rudiments. Eventually, the characterization of the TCR + cells of nude mice showed that these lymphocytes differ from the TCR0q3+ cells that are the products of differentiation in the thymus, from CD4+CD8ct[3÷ (double positive) precursors into CD4+CD8ct~ - or CD4-CD80qB÷ (single positive) mature progeny. These cells can be termed 'thymus differentiated and selected' (TDS) cells. The T cells of nude mice are not the result of the usual processes of T-cell differentiation and selection: however, cells with characteristics comparable to those of nude mice do exist in normal, euthymic mice. It has recently become apparent that, although their distribution in the body is very different from that of the TDS cells, the total
number of thymus-independent cells is very high. The aim of this review is to summarize what is presently understood about this extrathymic pathway. TCR + cells in the nude mice In nude mice, lymphocytes expressing the CD3-TCR complex are present in the spleen, lymph nodes 1-8, gut 9-IT, liver 12 and skin L~. They appear relatively late in ontogeny and increase in numbers only with aging 2,4'~°. Even in aged nude mice, the total number of T cells remains lower than that found in euthymic mice. The T cells of athymic animals may express either type of TCR, oq3 or ~'8. The distribution of the two cell types varies in different organs, between species (mouse or rat) and, within the same species, between different strains. Changes in the proportions of TCRot~+ and TCR~'8+ T cells also occur with aging"4'*% In contrast to euthymic mice, in which TCRoq3+ cells predominate in the thymus, spleen and lymph nodes, TCRo~ T cells are never the predominant population in nude mice; indeed, TCR?6+ T cells constitute a majority in some
© 1992, Elsevier Science Publishers lid, tlK.
Immunology Today
449
VoL 13 No. 11 19o2