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Lineage diversion of T cell receptor transgenic thymocytes revealed by lineage fate mapping.

Egawa T, Kreslavsky T, Littman DR, von Boehmer H - PLoS ONE (2008)

Bottom Line: TCR transgenic models have been used to study thymic selection and lineage commitment.Most TCR transgenic mice express the rearranged TCRalphabeta prematurely at the double negative stage and abnormal TCRalphabeta populations of T cells that are not easily detected in non-transgenic mice have been found in secondary lymphoid tissue of TCR transgenic mice.We found that most peripheral T cells with the HY-TCR in male mice have bypassed the RORgammat-positive CD4(+)8(+) (double positive, DP) stage to accumulate either as CD4(-)8(-) (double negative, DN) or as CD8alpha(+) T cells in lymph nodes or gut epithelium.

View Article: PubMed Central - PubMed

Affiliation: Molecular Pathogenesis Program, The Helen L. and Martin S. Kimmel Center for Biology and Medicine, Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, New York, USA.

ABSTRACT

Background: The binding of the T cell receptor (TCR) to major histocompatibility complex (MHC) molecules in the thymus determines fates of TCRalphabeta lymphocytes that subsequently home to secondary lymphoid tissue. TCR transgenic models have been used to study thymic selection and lineage commitment. Most TCR transgenic mice express the rearranged TCRalphabeta prematurely at the double negative stage and abnormal TCRalphabeta populations of T cells that are not easily detected in non-transgenic mice have been found in secondary lymphoid tissue of TCR transgenic mice.

Methodology and principal findings: To determine developmental pathways of TCR-transgenic thymocytes, we used Cre-LoxP-mediated fate mapping and show here that premature expression of a transgenic TCRalphabeta diverts some developing thymocytes to a developmental pathway which resembles that of gamma delta cells. We found that most peripheral T cells with the HY-TCR in male mice have bypassed the RORgammat-positive CD4(+)8(+) (double positive, DP) stage to accumulate either as CD4(-)8(-) (double negative, DN) or as CD8alpha(+) T cells in lymph nodes or gut epithelium. Likewise, DN TCRalphabeta cells in lymphoid tissue of female mice were not derived from DP thymocytes.

Conclusion: The results further support the hypothesis that the premature expression of the TCRalphabeta can divert DN thymocytes into gamma delta lineage cells.

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Fate mapping of lymph node T cells with the transgenic HY-TCR using RORγt-cre.CD4 and CD8α expression by gated HY (T3.70)+ lymph node cells (left column) is shown in the second column. EYFP expression by HY+CD4−CD8α−, HY+CD4+CD8α− and HY+CD4−CD8α+ T cells is shown.
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pone-0001512-g003: Fate mapping of lymph node T cells with the transgenic HY-TCR using RORγt-cre.CD4 and CD8α expression by gated HY (T3.70)+ lymph node cells (left column) is shown in the second column. EYFP expression by HY+CD4−CD8α−, HY+CD4+CD8α− and HY+CD4−CD8α+ T cells is shown.

Mentions: In female HY TCR transgenic mice, single positive thymocytes and lymph node T cells that express the transgenic TCR and either CD4 or CD8 co-receptor were all EYFP-positive and thus derived from DP thymocytes (Figures 3 and S2). The CD4+ subset includes cells with relatively high levels of the transgenic TCR. However, the generation of these cells requires co-expression of endogenous TCRα chains since such CD4+8− T cells are absent in female HY TCR transgenic mice on the RAG-2−/− background [16]. In contrast to WT mice, there was a substantial number of DN cells that expressed TCRαβ in female transgenic mice. The vast majority of these cells was EYFP-negative and thus was not derived from DP thymocytes. TCRαβ-expressing DN cells were also detected intrathymically (Figure S2). In male HY-TCR transgenic mice, T cells with the transgenic TCR exhibited an even more abnormal phenotypic pattern: the vast majority of DN cells and CD8+ cells, the latter expressing relatively low levels of CD8β, were EYFP-negative and hence were not derived from DP thymocytes.


Lineage diversion of T cell receptor transgenic thymocytes revealed by lineage fate mapping.

Egawa T, Kreslavsky T, Littman DR, von Boehmer H - PLoS ONE (2008)

Fate mapping of lymph node T cells with the transgenic HY-TCR using RORγt-cre.CD4 and CD8α expression by gated HY (T3.70)+ lymph node cells (left column) is shown in the second column. EYFP expression by HY+CD4−CD8α−, HY+CD4+CD8α− and HY+CD4−CD8α+ T cells is shown.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211402&req=5

pone-0001512-g003: Fate mapping of lymph node T cells with the transgenic HY-TCR using RORγt-cre.CD4 and CD8α expression by gated HY (T3.70)+ lymph node cells (left column) is shown in the second column. EYFP expression by HY+CD4−CD8α−, HY+CD4+CD8α− and HY+CD4−CD8α+ T cells is shown.
Mentions: In female HY TCR transgenic mice, single positive thymocytes and lymph node T cells that express the transgenic TCR and either CD4 or CD8 co-receptor were all EYFP-positive and thus derived from DP thymocytes (Figures 3 and S2). The CD4+ subset includes cells with relatively high levels of the transgenic TCR. However, the generation of these cells requires co-expression of endogenous TCRα chains since such CD4+8− T cells are absent in female HY TCR transgenic mice on the RAG-2−/− background [16]. In contrast to WT mice, there was a substantial number of DN cells that expressed TCRαβ in female transgenic mice. The vast majority of these cells was EYFP-negative and thus was not derived from DP thymocytes. TCRαβ-expressing DN cells were also detected intrathymically (Figure S2). In male HY-TCR transgenic mice, T cells with the transgenic TCR exhibited an even more abnormal phenotypic pattern: the vast majority of DN cells and CD8+ cells, the latter expressing relatively low levels of CD8β, were EYFP-negative and hence were not derived from DP thymocytes.

Bottom Line: TCR transgenic models have been used to study thymic selection and lineage commitment.Most TCR transgenic mice express the rearranged TCRalphabeta prematurely at the double negative stage and abnormal TCRalphabeta populations of T cells that are not easily detected in non-transgenic mice have been found in secondary lymphoid tissue of TCR transgenic mice.We found that most peripheral T cells with the HY-TCR in male mice have bypassed the RORgammat-positive CD4(+)8(+) (double positive, DP) stage to accumulate either as CD4(-)8(-) (double negative, DN) or as CD8alpha(+) T cells in lymph nodes or gut epithelium.

View Article: PubMed Central - PubMed

Affiliation: Molecular Pathogenesis Program, The Helen L. and Martin S. Kimmel Center for Biology and Medicine, Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, New York, USA.

ABSTRACT

Background: The binding of the T cell receptor (TCR) to major histocompatibility complex (MHC) molecules in the thymus determines fates of TCRalphabeta lymphocytes that subsequently home to secondary lymphoid tissue. TCR transgenic models have been used to study thymic selection and lineage commitment. Most TCR transgenic mice express the rearranged TCRalphabeta prematurely at the double negative stage and abnormal TCRalphabeta populations of T cells that are not easily detected in non-transgenic mice have been found in secondary lymphoid tissue of TCR transgenic mice.

Methodology and principal findings: To determine developmental pathways of TCR-transgenic thymocytes, we used Cre-LoxP-mediated fate mapping and show here that premature expression of a transgenic TCRalphabeta diverts some developing thymocytes to a developmental pathway which resembles that of gamma delta cells. We found that most peripheral T cells with the HY-TCR in male mice have bypassed the RORgammat-positive CD4(+)8(+) (double positive, DP) stage to accumulate either as CD4(-)8(-) (double negative, DN) or as CD8alpha(+) T cells in lymph nodes or gut epithelium. Likewise, DN TCRalphabeta cells in lymphoid tissue of female mice were not derived from DP thymocytes.

Conclusion: The results further support the hypothesis that the premature expression of the TCRalphabeta can divert DN thymocytes into gamma delta lineage cells.

Show MeSH