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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 T cells from WT and HY-TCR transgenic mice expressing endogenous TCRα using RORγt-cre.CD4 and CD8α expression by gated HY (T3.70)− TCRβ+ lymph node cells (left column) is shown in the second column. EYFP expression by HY−CD4+ and HY−CD8α+ T cells is shown.
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pone-0001512-g001: Fate mapping of T cells from WT and HY-TCR transgenic mice expressing endogenous TCRα using RORγt-cre.CD4 and CD8α expression by gated HY (T3.70)− TCRβ+ lymph node cells (left column) is shown in the second column. EYFP expression by HY−CD4+ and HY−CD8α+ T cells is shown.

Mentions: In RORγt-cre;ROSA26-stop-EYFP mice on a non-TCR transgenic background, practically all extrathymic cells with surface TCRβ chains were EYFP+ and thus derived from RORγt+ cells such as DP thymocytes (Figure 1). The same EYFP expression pattern was observed in extrathymic T cells from lymph nodes of male and female HY-TCR transgenic mice that did not express the transgenic TCR because of replacement of transgenic TCRα by endogenous TCRα chains (Figure 1) [14], [15]. This indicates that, after endogenous TCRα rearrangement in TCR transgenic mice, cells with new TCRs composed of transgenic TCRβ chain and endogenous TCRα chains develop in a similar pathway as they do in normal mice. Cells with the phenotype of extrathymic T cells were also found intrathymically (Figure S1) making it likely that they are all derived from RORγt+ DP thymocytes. Thus, in spite of the thymic cortex being largely devoid of DP thymocytes in male mice, some cells develop normally if they escape deletion by the early expression of endogenous TCRα chains.


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 T cells from WT and HY-TCR transgenic mice expressing endogenous TCRα using RORγt-cre.CD4 and CD8α expression by gated HY (T3.70)− TCRβ+ lymph node cells (left column) is shown in the second column. EYFP expression by HY−CD4+ and HY−CD8α+ T cells is shown.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0001512-g001: Fate mapping of T cells from WT and HY-TCR transgenic mice expressing endogenous TCRα using RORγt-cre.CD4 and CD8α expression by gated HY (T3.70)− TCRβ+ lymph node cells (left column) is shown in the second column. EYFP expression by HY−CD4+ and HY−CD8α+ T cells is shown.
Mentions: In RORγt-cre;ROSA26-stop-EYFP mice on a non-TCR transgenic background, practically all extrathymic cells with surface TCRβ chains were EYFP+ and thus derived from RORγt+ cells such as DP thymocytes (Figure 1). The same EYFP expression pattern was observed in extrathymic T cells from lymph nodes of male and female HY-TCR transgenic mice that did not express the transgenic TCR because of replacement of transgenic TCRα by endogenous TCRα chains (Figure 1) [14], [15]. This indicates that, after endogenous TCRα rearrangement in TCR transgenic mice, cells with new TCRs composed of transgenic TCRβ chain and endogenous TCRα chains develop in a similar pathway as they do in normal mice. Cells with the phenotype of extrathymic T cells were also found intrathymically (Figure S1) making it likely that they are all derived from RORγt+ DP thymocytes. Thus, in spite of the thymic cortex being largely devoid of DP thymocytes in male mice, some cells develop normally if they escape deletion by the early expression of endogenous TCRα chains.

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