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B cells participate in thymic negative selection of murine auto-reactive CD4+ T cells.

Frommer F, Waisman A - PLoS ONE (2010)

Bottom Line: It is well documented that thymic epithelial cells participate in the process of negative selection in the thymus.Using a unique mouse model we show that B cells induce negative selection of self-reactive thymocytes in a process that leads to the deletion of these cells whereas regulatory T cells are spared.These findings have direct implication in autoimmunity, as expression of a myelin antigen by B cells in the thymus renders the mice resistant to autoimmune inflammation of the CNS.

View Article: PubMed Central - PubMed

Affiliation: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.

ABSTRACT
It is well documented that thymic epithelial cells participate in the process of negative selection in the thymus. In recent years it was reported that also dendritic cells enter the thymus and contribute to this process, thus allowing for the depletion of thymocytes that are specific to peripherally expressed self-antigens. Here we report that also B cells may take part in the elimination of auto-reactive thymocytes. Using a unique mouse model we show that B cells induce negative selection of self-reactive thymocytes in a process that leads to the deletion of these cells whereas regulatory T cells are spared. These findings have direct implication in autoimmunity, as expression of a myelin antigen by B cells in the thymus renders the mice resistant to autoimmune inflammation of the CNS.

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Related in: MedlinePlus

Deletion of 2D2 CD4+ T cells in the thymus is specifically induced by B cells.LN of 2D2 and 2D2/JHT (left row) as well as BMOG/2D2 and BMOG/2D2/JHT (right row) mice were analyzed by FACS analysis for presence of CD4+ Vα3.2+ T cells. Genotypes and antibodies used are as indicated. Cell surface markers are shown as coordinates. Cells were gated on live lymphocytes. Numbers besides gates or in quadrants indicate percent positive cells in each.
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pone-0015372-g002: Deletion of 2D2 CD4+ T cells in the thymus is specifically induced by B cells.LN of 2D2 and 2D2/JHT (left row) as well as BMOG/2D2 and BMOG/2D2/JHT (right row) mice were analyzed by FACS analysis for presence of CD4+ Vα3.2+ T cells. Genotypes and antibodies used are as indicated. Cell surface markers are shown as coordinates. Cells were gated on live lymphocytes. Numbers besides gates or in quadrants indicate percent positive cells in each.

Mentions: We were wondering whether the very efficient negative selection we observed in the thymi of BMOG/2D2 mice is in fact the result of peptide expression by other APCs in the thymus. Previously, we have ruled out the possibility that DCs and macrophages in the BMOG mice present the MOG peptide, as we found that they were not able to trigger 2D2 TCR expressing cells in vitro [19]. But in the thymus, there are specialized cells, such as medullary thymic epithelial cells (mTEC) that participate in the process of negative selection, implicating the risk of unspecific MOG presentation in the thymus. To investigate whether the Cre-recombinase in BMOG mice is unspecifically expressed in cells other than B cells, and therefore leads to negative selection by non-B cells, we crossed BMOG/2D2 mice to B cell-deficient JHT mice. In JHT mice, the whole JH locus was deleted using the Cre/loxP system, leading to mice that are not capable to rearrange the heavy chain locus, and are therefore absolutely devoid of B cells [22]. As seen in Fig. 2, BMOG/2D2 mice crossed to the JHT mutant mice show a T cell development that is comparable to that of 2D2 WT mice. These findings demonstrate that the negative selection seen in BMOG/2D2 mice is indeed the result of the MOG peptide presented by MHCII of B cells, and not by unspecific expression of CD19-Cre, that would lead to Cre expression and thus MOG presentation by non-B cells in the thymus.


B cells participate in thymic negative selection of murine auto-reactive CD4+ T cells.

Frommer F, Waisman A - PLoS ONE (2010)

Deletion of 2D2 CD4+ T cells in the thymus is specifically induced by B cells.LN of 2D2 and 2D2/JHT (left row) as well as BMOG/2D2 and BMOG/2D2/JHT (right row) mice were analyzed by FACS analysis for presence of CD4+ Vα3.2+ T cells. Genotypes and antibodies used are as indicated. Cell surface markers are shown as coordinates. Cells were gated on live lymphocytes. Numbers besides gates or in quadrants indicate percent positive cells in each.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2958132&req=5

pone-0015372-g002: Deletion of 2D2 CD4+ T cells in the thymus is specifically induced by B cells.LN of 2D2 and 2D2/JHT (left row) as well as BMOG/2D2 and BMOG/2D2/JHT (right row) mice were analyzed by FACS analysis for presence of CD4+ Vα3.2+ T cells. Genotypes and antibodies used are as indicated. Cell surface markers are shown as coordinates. Cells were gated on live lymphocytes. Numbers besides gates or in quadrants indicate percent positive cells in each.
Mentions: We were wondering whether the very efficient negative selection we observed in the thymi of BMOG/2D2 mice is in fact the result of peptide expression by other APCs in the thymus. Previously, we have ruled out the possibility that DCs and macrophages in the BMOG mice present the MOG peptide, as we found that they were not able to trigger 2D2 TCR expressing cells in vitro [19]. But in the thymus, there are specialized cells, such as medullary thymic epithelial cells (mTEC) that participate in the process of negative selection, implicating the risk of unspecific MOG presentation in the thymus. To investigate whether the Cre-recombinase in BMOG mice is unspecifically expressed in cells other than B cells, and therefore leads to negative selection by non-B cells, we crossed BMOG/2D2 mice to B cell-deficient JHT mice. In JHT mice, the whole JH locus was deleted using the Cre/loxP system, leading to mice that are not capable to rearrange the heavy chain locus, and are therefore absolutely devoid of B cells [22]. As seen in Fig. 2, BMOG/2D2 mice crossed to the JHT mutant mice show a T cell development that is comparable to that of 2D2 WT mice. These findings demonstrate that the negative selection seen in BMOG/2D2 mice is indeed the result of the MOG peptide presented by MHCII of B cells, and not by unspecific expression of CD19-Cre, that would lead to Cre expression and thus MOG presentation by non-B cells in the thymus.

Bottom Line: It is well documented that thymic epithelial cells participate in the process of negative selection in the thymus.Using a unique mouse model we show that B cells induce negative selection of self-reactive thymocytes in a process that leads to the deletion of these cells whereas regulatory T cells are spared.These findings have direct implication in autoimmunity, as expression of a myelin antigen by B cells in the thymus renders the mice resistant to autoimmune inflammation of the CNS.

View Article: PubMed Central - PubMed

Affiliation: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.

ABSTRACT
It is well documented that thymic epithelial cells participate in the process of negative selection in the thymus. In recent years it was reported that also dendritic cells enter the thymus and contribute to this process, thus allowing for the depletion of thymocytes that are specific to peripherally expressed self-antigens. Here we report that also B cells may take part in the elimination of auto-reactive thymocytes. Using a unique mouse model we show that B cells induce negative selection of self-reactive thymocytes in a process that leads to the deletion of these cells whereas regulatory T cells are spared. These findings have direct implication in autoimmunity, as expression of a myelin antigen by B cells in the thymus renders the mice resistant to autoimmune inflammation of the CNS.

Show MeSH
Related in: MedlinePlus