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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.

Show MeSH
Fate mapping of IEL from WT and HY-TCR transgenic mice expressing endogenous TCRα using RORγt-cre.CD4 and CD8α expression by gated HY (T3.70)− TCRβ+ IEL (left column) is shown in the second column. CD8β expression by gated CD8α+ cells (second column) is shown in the third column. EYFP expression by HY−CD4+, HY−CD8αα+ and HY−CD8αβ+ T cells is shown.
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pone-0001512-g002: Fate mapping of IEL from WT and HY-TCR transgenic mice expressing endogenous TCRα using RORγt-cre.CD4 and CD8α expression by gated HY (T3.70)− TCRβ+ IEL (left column) is shown in the second column. CD8β expression by gated CD8α+ cells (second column) is shown in the third column. EYFP expression by HY−CD4+, HY−CD8αα+ and HY−CD8αβ+ T cells is shown.

Mentions: The pattern of reporter expression observed in IEL bearing endogenous TCRα chains was very similar to that obtained in lymph node T cells, with the exception that IEL contained a high proportion of CD8αα cells with TCRαβ that, like CD8αβ IEL, were EYFP+ (Figure 2). These results confirm earlier data on IEL in WT mice and in addition indicate that in TCR transgenic mice IEL with receptors other than the transgenic TCR are derived from RORγt+ precursors, presumably DP thymocytes. In contrast, the vast majority of IEL with TCRγδ was EYFP-negative in WT as well as in TCR transgenic mice (Figures 2 and S3). Thus, T cells with receptors other than the HY transgenic TCR, while they are relatively rare in TCR transgenic mice, develop along the same pathway as T cells in WT mice, indicating that normal pathways of T cell differentiation are operative in TCR transgenic mice.


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 IEL from WT and HY-TCR transgenic mice expressing endogenous TCRα using RORγt-cre.CD4 and CD8α expression by gated HY (T3.70)− TCRβ+ IEL (left column) is shown in the second column. CD8β expression by gated CD8α+ cells (second column) is shown in the third column. EYFP expression by HY−CD4+, HY−CD8αα+ and HY−CD8αβ+ T cells is shown.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0001512-g002: Fate mapping of IEL from WT and HY-TCR transgenic mice expressing endogenous TCRα using RORγt-cre.CD4 and CD8α expression by gated HY (T3.70)− TCRβ+ IEL (left column) is shown in the second column. CD8β expression by gated CD8α+ cells (second column) is shown in the third column. EYFP expression by HY−CD4+, HY−CD8αα+ and HY−CD8αβ+ T cells is shown.
Mentions: The pattern of reporter expression observed in IEL bearing endogenous TCRα chains was very similar to that obtained in lymph node T cells, with the exception that IEL contained a high proportion of CD8αα cells with TCRαβ that, like CD8αβ IEL, were EYFP+ (Figure 2). These results confirm earlier data on IEL in WT mice and in addition indicate that in TCR transgenic mice IEL with receptors other than the transgenic TCR are derived from RORγt+ precursors, presumably DP thymocytes. In contrast, the vast majority of IEL with TCRγδ was EYFP-negative in WT as well as in TCR transgenic mice (Figures 2 and S3). Thus, T cells with receptors other than the HY transgenic TCR, while they are relatively rare in TCR transgenic mice, develop along the same pathway as T cells in WT mice, indicating that normal pathways of T cell differentiation are operative in TCR transgenic mice.

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