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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 IEL T cells with the transgenic HY-TCR using RORγt-cre.CD4 and CD8α expression by gated HY (T3.70)+ 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−CD8α−, HY+CD4+, HY+CD8αα+ and HY+CD8αβ+ T cells is shown.
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pone-0001512-g004: Fate mapping of IEL T cells with the transgenic HY-TCR using RORγt-cre.CD4 and CD8α expression by gated HY (T3.70)+ 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−CD8α−, HY+CD4+, HY+CD8αα+ and HY+CD8αβ+ T cells is shown.

Mentions: Similar abnormalities were noted in IEL, among which DN cells comprised a much larger compartment in female HY-TCR transgenic compared to WT mice (Figure 4); the majority of DN cells with the transgenic TCR did not develop through RORγt-expressing DP thymocytes, similar to most CD8αα cells that were likewise mostly EYFP-negative. However, in female mice, a substantial number of EYFP-positive cells was also present among HY+ IEL that were either DN or CD8αα suggesting that induction of these atypical lineages could have occurred at the DP stage. In contrast, all CD8αβ-positive cells with the transgenic TCR were RORγt+ cell-derived. In male HY-TCR transgenic mice, practically all DN, CD8αα and a majority of CD8αβ cells were EYFP-negative and hence were not derived from RORγt+ DP thymocytes. This was especially true for the exaggerated number of CD8αα IEL that in WT mice were all derived from RORγt+ precursors (Figures 2 and 4). The notion that most CD8α+ HY-TCR-expressing cells in IEL have a different origin than CD8α+ IEL of WT mice is supported by the finding that only the former expressed uniformly low levels of CD5 (data not shown).


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 T cells with the transgenic HY-TCR using RORγt-cre.CD4 and CD8α expression by gated HY (T3.70)+ 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−CD8α−, 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-g004: Fate mapping of IEL T cells with the transgenic HY-TCR using RORγt-cre.CD4 and CD8α expression by gated HY (T3.70)+ 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−CD8α−, HY+CD4+, HY+CD8αα+ and HY+CD8αβ+ T cells is shown.
Mentions: Similar abnormalities were noted in IEL, among which DN cells comprised a much larger compartment in female HY-TCR transgenic compared to WT mice (Figure 4); the majority of DN cells with the transgenic TCR did not develop through RORγt-expressing DP thymocytes, similar to most CD8αα cells that were likewise mostly EYFP-negative. However, in female mice, a substantial number of EYFP-positive cells was also present among HY+ IEL that were either DN or CD8αα suggesting that induction of these atypical lineages could have occurred at the DP stage. In contrast, all CD8αβ-positive cells with the transgenic TCR were RORγt+ cell-derived. In male HY-TCR transgenic mice, practically all DN, CD8αα and a majority of CD8αβ cells were EYFP-negative and hence were not derived from RORγt+ DP thymocytes. This was especially true for the exaggerated number of CD8αα IEL that in WT mice were all derived from RORγt+ precursors (Figures 2 and 4). The notion that most CD8α+ HY-TCR-expressing cells in IEL have a different origin than CD8α+ IEL of WT mice is supported by the finding that only the former expressed uniformly low levels of CD5 (data not shown).

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