Application for R and D 100 award: The UNWRAP SYSTEM

Mosley, W.C.

doi:10.2172/5366417

Cited by 9 publications

(14 citation statements)

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“…If CD3-IEL are precursors of extrathymic CD3+ IEL, their development, although in some ways different, may show some similarity to the development of CD3-thymocytes into CD3+ thymocytes. The differences are marked, as others have shown that the double-positive stage (CD4'-CD8+) is probably not involved in extrathymic IEL development, because this subset appears fairly late in ontogeny ( [31] and data not shown). Furthermore, most CD3-IEL (unlike CD3-thymocytes) lack CD5, CD2 and CD28 (data not shown).…”

Section: Discussionmentioning

confidence: 76%

“…A recent study using a bone marrow chimera model showed that CD3+CD8+aP IEL may also be extrathymically derived [19]. In contrast, when we examined the phenotype of the newly donor derived CD3+CD8+ IEL on day 23 after bone marrow reconstitution, virtually all CD3+CD8+ IEL were y8 TCR+ and CD8+aa (Fig.…”

Section: Kinetics Of Iel In Bone Marrow Chimeras Suggest That Cdscds-mentioning

confidence: 92%

“…lb). We chose to concentrate on these two antigens for markers of extrathymic differentiation as both y6 and a@ TCR-expressing IEL may be extrathymically derived [18][19][20], and present evidence suggests that it is the CD8aa subset, regardless of TCR expression, that are mostly extrathymically derived [2][3][4]. At 2.5 weeks of age, a period prior to the increase in IEL number, the majority of IEL were CD3-.…”

Section: Ontogeny Of Cd3+ and Cds+ Ielmentioning

confidence: 99%

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CD3⁻CD8⁺ intestinal intraepithelial lymphocytes (IEL) and the extrathymic development of IEL

et al. 1994

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Present evidence suggests that a majority of murine CD3+ intraepithelial intestinal lymphocytes (IEL) are extrathymically derived T cells and that these extrathymically derived IEL phenotypically express the CD8 homodimer (CD8 alpha alpha). Recently, CD3- IEL have been reported to express the recombination activating gene (RAG-1), suggesting that precursors to extrathymically derived CD3+CD8+ alpha alpha IEL exist on the intestinal epithelium. To study in detail whether these CD3-IEL can develop into CD3+CD8+ alpha alpha IEL, we analyzed the CD3-IEL subset and found that it can be separated into two subsets, namely CD3-CD8- and CD3-CD8+ IEL. We show that (1) CD3-CD8- IEL are mostly small, non-granular and phenotypically Pgp-1+ IL-2R+ B220-, while CD3-CD8+ IEL are mostly large, granular and phenotypically Pgp-1- IL-2R+ B220+, (2) CD(3-)-CD8+ IEL express the RAG-1 gene, and (3) CD3-CD8-, CD3-CD8+ and CD3+CD8+ alpha alpha IEL, respectively, appear sequentially in normal ontogeny and in bone marrow-reconstituted thymectomized radiation chimeras. In the latter, virtually all CD3+CD8+ alpha alpha IEL expressed the gamma delta T cell receptor (TCR), but not the alpha beta TCR. From this and what is presently known about T cell development, we propose that CD3-CD8+ IEL are an intermediate in extrathymic IEL development and that the development of extrathymically derived IEL occurs at the intestinal epithelium from CD3-CD8- to CD3-CD8+ to CD3+(gamma delta TCR)CD8+ alpha alpha.

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Section: Discussionmentioning

confidence: 76%

Section: Kinetics Of Iel In Bone Marrow Chimeras Suggest That Cdscds-mentioning

confidence: 92%

Section: Ontogeny Of Cd3+ and Cds+ Ielmentioning

confidence: 99%

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CD3⁻CD8⁺ intestinal intraepithelial lymphocytes (IEL) and the extrathymic development of IEL

et al. 1994

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“…These data have led to the hypothesis that signals from the preTcR, delivered primarily through Lck [20], are required for the progression of immature thymocytes committed to the TcRab lineage to progress to the CD4'CDS' stage. We now report that similar mechanisms may act to control development of a subset of TcRa(3' IEL that are likely to mature extrathymically [S, 13,601. Hence both TcRap' IEL and thymocytes require Lck, or in its absence Fyn, to mature to the CD3' stage.…”

Section: Discussionmentioning

confidence: 99%

Differential contribution of Lck and Fyn protein tyrosine kinases to intraepithelial lymphocyte development

et al. 1997

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The developmental stages and the role of protein tyrosine kinases (PTK) in the maturation of CD3+CD8 alpha alpha+ intraepithelial lymphocytes (IEL) have not been extensively characterized. However, comparisons of thymic and extrathymic T cell development indicate that these processes involve some distinct signaling and selection events. We used mice deficient in Lck, Fyn, or both Lck and Fyn to analyze the role that these src-family PTK play in IEL development. In contrast to thymocyte development, we found that all IEL subsets develop in mice deficient for either kinase alone. However, lck-/- animals exhibited reduced numbers of TcR alphabeta+ CD8alpha alpha+ IEL, indicating that Lck is important in the development of these cells. Mice which lack both Lck and Fyn fail to generate TcR alphabeta+ IEL, suggesting that signaling through the preTcR, mediated by Lck and, to a lesser extent Fyn, is required for maturation of all TcR alphabeta+ IEL lineages. Interestingly, a small population of TcR gammadelta+ CD8 alpha alpha+ cells are apparent in lck-/-fyn-/- animals, demonstrating that TcR alphabeta+ CD8 alpha alpha+ and TcR gammadelta+ CD8alpha alpha+ IEL have distinct PTK requirements for their development or expansion. CD3-CD8alpha- CD44+ and CD3-CD8alpha alpha+ CD16/32+ B220+ cells comprise the majority of IEL in both lck-/- fyn-/- and rag -/- mice, while they are poorly represented in wildtype controls. Comparison of the cell surface phenotype of these putative precursor IEL in lck-/- fyn-/- and rag-/- animals suggests that IEL maturation in these animals is arrested at an equivalent developmental stage. Overall, the data presented demonstrate that signals mediated by Lck or Fyn direct TcR alphabeta+ CD8alpha alpha+ IEL maturation but are dispensable for the development of TcR gammadelta+ CD8 alpha alpha+ IEL.

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“…Extrathymically differentiated T cells have been reported in athymic nude mice [7-101 and neonatally thymectomized mice [ll-131. It has also been reported that intestinal intraepithelial lymphocytes(i-IEL) [14][15][16][17][18] and liver mononuclear cells [19,201 of euthymic mice contain extrathymically differentiated T cells. The T cells which [I 114801 differentiated through extrathymic pathway contain cells expressing TcR Vp capable of recognizing self superantigens [7,8,13,16,, although such autoreactive Vpbearing T cells are deleted in the intrathymic pathway of T cell differentiation [24-271. It has been reported that the thymus produces several cytokines, including IL-1, IL-6, and IL-7, and the cytokines may have important roles in the intrathymic T cell differentiation [28-341. In the present study, we investigated the influence of the thymus-derived cytokines on extrathymic T cell differentiation by analyzing athymic nude mice implanted with a fetal thymus-enclosed diffusion chamber (FTEDC).…”

Section: Introductionmentioning

confidence: 99%

Thymus‐derived cytokine(s) including interleukin‐7 induce increase of T cell receptor α/β⁺ CD4⁻CD8⁻ T cells which are extrathymically differentiated in athymic nude mice

et al. 1993

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Extrathymic T cell differentiation pathways have been reported, although the thymus is the main site of T cell differentiation. The thymus is also known to produce several cytokines that induce proliferation of thymocytes. In the present study, we investigated the influence of thymus-derived cytokines on extrathymic T cell differentiation by intraperitoneal implantation with a diffusion chamber which encloses fetal thymus (we named it fetal thymus-enclosed diffusion chamber, FTEDC) in athymic BALB/c nu/nu mice. Increase in number of T cells bearing T cell receptor (TcR) alpha/beta was detected in lymph nodes and spleens of FTEDC-implanted nude mice 1 week after implantation, whereas no such increase was detected in control nude mice implanted with a diffusion chamber without thymus. The FTEDC-induced increase of T cells was suppressed by intraperitoneal injection of anti-interleukin-7 monoclonal antibody (mAb). The TcR alpha/beta T cells in FTEDC-implanted BALB/c nu/nu mice preferentially expressed V beta 11, although V beta 11-positive T cells are deleted in the thymus of euthymic BALB/c mice by clonal elimination of self-super-antigen Dvb11-specific T cells. TcR alpha/beta T cells in FTEDC-implanted nude mice were of CD4-CD8- phenotype and showed no proliferative response against anti-TcR monoclonal antibody stimulation. These results suggest that the thymus can induce extrathymic T cell differentiation through the influence of thymus-derived cytokine(s) including interleukin-7, and that such extrathymically differentiated T cells have acquired only a little or no ability for proliferation when they recognize antigen by their TcR.

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Application for R and D 100 award: The UNWRAP SYSTEM

Cited by 9 publications

References 0 publications

CD3⁻CD8⁺ intestinal intraepithelial lymphocytes (IEL) and the extrathymic development of IEL

CD3⁻CD8⁺ intestinal intraepithelial lymphocytes (IEL) and the extrathymic development of IEL

Differential contribution of Lck and Fyn protein tyrosine kinases to intraepithelial lymphocyte development

Thymus‐derived cytokine(s) including interleukin‐7 induce increase of T cell receptor α/β⁺ CD4⁻CD8⁻ T cells which are extrathymically differentiated in athymic nude mice

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Application for R and D 100 award: The UNWRAP SYSTEM

Cited by 9 publications

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CD3−CD8+ intestinal intraepithelial lymphocytes (IEL) and the extrathymic development of IEL

CD3−CD8+ intestinal intraepithelial lymphocytes (IEL) and the extrathymic development of IEL

Differential contribution of Lck and Fyn protein tyrosine kinases to intraepithelial lymphocyte development

Thymus‐derived cytokine(s) including interleukin‐7 induce increase of T cell receptor α/β+ CD4−CD8− T cells which are extrathymically differentiated in athymic nude mice

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CD3⁻CD8⁺ intestinal intraepithelial lymphocytes (IEL) and the extrathymic development of IEL

CD3⁻CD8⁺ intestinal intraepithelial lymphocytes (IEL) and the extrathymic development of IEL

Thymus‐derived cytokine(s) including interleukin‐7 induce increase of T cell receptor α/β⁺ CD4⁻CD8⁻ T cells which are extrathymically differentiated in athymic nude mice