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In situ tolerance within the central nervous system as a mechanism for preventing autoimmunity.

Brabb T, von Dassow P, Ordonez N, Schnabel B, Duke B, Goverman J - J. Exp. Med. (2000)

Bottom Line: Transgenic T cells isolated from the CNS that are specific for non-CNS antigens are phenotypically naive and proliferate robustly to antigenic stimulation in vitro.Strikingly, transgenic T cells isolated from the CNS that are specific for myelin basic protein (MBP) are also primarily phenotypically naive but are unresponsive to antigenic stimulation in vitro.These results indicate that naive MBP-specific T cells can traffic to the CNS but do not trigger autoimmunity because they undergo tolerance induction in situ.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biotechnology, University of Washington, Seattle, Washington 98195, USA.

ABSTRACT
Multiple sclerosis (MS) is believed to be an autoimmune disease in which autoreactive T cells infiltrate the central nervous system (CNS). Animal models of MS have shown that CNS-specific T cells are present in the peripheral T cell repertoire of healthy mice and cause autoimmune disease only when they are activated by immunization. T cell entry into the CNS is thought to require some form of peripheral activation because the blood-brain barrier prohibits trafficking of this tissue by naive cells. We report here that naive T cells can traffic to the CNS without prior activation. Comparable numbers of T cells are found in the CNS of both healthy recombinase activating gene (Rag)(-/)- T cell receptor (TCR) transgenic mice and nontransgenic mice even when the transgenic TCR is specific for a CNS antigen. Transgenic T cells isolated from the CNS that are specific for non-CNS antigens are phenotypically naive and proliferate robustly to antigenic stimulation in vitro. Strikingly, transgenic T cells isolated from the CNS that are specific for myelin basic protein (MBP) are also primarily phenotypically naive but are unresponsive to antigenic stimulation in vitro. Mononuclear cells from the CNS of MBP TCR transgenic but not nontransgenic mice can suppress the response of peripheral MBP-specific T cells in vitro. These results indicate that naive MBP-specific T cells can traffic to the CNS but do not trigger autoimmunity because they undergo tolerance induction in situ.

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T cells in the CNS of TCR transgenic mice have a predominately naive phenotype. T cells were harvested from the CNS (solid lines) and spleen (dotted lines) as described in Materials and Methods, and stained with monoclonal antibodies specific for TCR, CD44, and CD45RB. The indicated percentage of naive CNS T cells represents the average percentage of TCR+ cells ± one SD that are neither CD44hi nor CD45RBlo (as indicated by the bars).
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Figure 2: T cells in the CNS of TCR transgenic mice have a predominately naive phenotype. T cells were harvested from the CNS (solid lines) and spleen (dotted lines) as described in Materials and Methods, and stained with monoclonal antibodies specific for TCR, CD44, and CD45RB. The indicated percentage of naive CNS T cells represents the average percentage of TCR+ cells ± one SD that are neither CD44hi nor CD45RBlo (as indicated by the bars).

Mentions: Previous studies in nontransgenic mice indicated that only activated T cells cross the blood–brain barrier 7910. To investigate whether the T cells found in the CNS of TCR transgenic mice also display an activated phenotype, T cell populations in 4–7-wk-old nontransgenic (controls) and Rag−/− MBP TCR transgenic mice were analyzed using antibodies specific for cell-surface activation/memory markers. In nontransgenic mice, the majority of CNS T cells expressed high levels of CD44 as well as low levels of CD45RB (Fig. 2) and high levels of CD49d (data not shown), consistent with an activated/memory phenotype. Peripheral T cells from nontransgenic mice expressed significantly lower levels of these activation/memory markers compared with CNS T cells (P = 0.002). These observations are consistent with earlier studies showing that the CNS is preferentially trafficked by activated T cells.


In situ tolerance within the central nervous system as a mechanism for preventing autoimmunity.

Brabb T, von Dassow P, Ordonez N, Schnabel B, Duke B, Goverman J - J. Exp. Med. (2000)

T cells in the CNS of TCR transgenic mice have a predominately naive phenotype. T cells were harvested from the CNS (solid lines) and spleen (dotted lines) as described in Materials and Methods, and stained with monoclonal antibodies specific for TCR, CD44, and CD45RB. The indicated percentage of naive CNS T cells represents the average percentage of TCR+ cells ± one SD that are neither CD44hi nor CD45RBlo (as indicated by the bars).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2193284&req=5

Figure 2: T cells in the CNS of TCR transgenic mice have a predominately naive phenotype. T cells were harvested from the CNS (solid lines) and spleen (dotted lines) as described in Materials and Methods, and stained with monoclonal antibodies specific for TCR, CD44, and CD45RB. The indicated percentage of naive CNS T cells represents the average percentage of TCR+ cells ± one SD that are neither CD44hi nor CD45RBlo (as indicated by the bars).
Mentions: Previous studies in nontransgenic mice indicated that only activated T cells cross the blood–brain barrier 7910. To investigate whether the T cells found in the CNS of TCR transgenic mice also display an activated phenotype, T cell populations in 4–7-wk-old nontransgenic (controls) and Rag−/− MBP TCR transgenic mice were analyzed using antibodies specific for cell-surface activation/memory markers. In nontransgenic mice, the majority of CNS T cells expressed high levels of CD44 as well as low levels of CD45RB (Fig. 2) and high levels of CD49d (data not shown), consistent with an activated/memory phenotype. Peripheral T cells from nontransgenic mice expressed significantly lower levels of these activation/memory markers compared with CNS T cells (P = 0.002). These observations are consistent with earlier studies showing that the CNS is preferentially trafficked by activated T cells.

Bottom Line: Transgenic T cells isolated from the CNS that are specific for non-CNS antigens are phenotypically naive and proliferate robustly to antigenic stimulation in vitro.Strikingly, transgenic T cells isolated from the CNS that are specific for myelin basic protein (MBP) are also primarily phenotypically naive but are unresponsive to antigenic stimulation in vitro.These results indicate that naive MBP-specific T cells can traffic to the CNS but do not trigger autoimmunity because they undergo tolerance induction in situ.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biotechnology, University of Washington, Seattle, Washington 98195, USA.

ABSTRACT
Multiple sclerosis (MS) is believed to be an autoimmune disease in which autoreactive T cells infiltrate the central nervous system (CNS). Animal models of MS have shown that CNS-specific T cells are present in the peripheral T cell repertoire of healthy mice and cause autoimmune disease only when they are activated by immunization. T cell entry into the CNS is thought to require some form of peripheral activation because the blood-brain barrier prohibits trafficking of this tissue by naive cells. We report here that naive T cells can traffic to the CNS without prior activation. Comparable numbers of T cells are found in the CNS of both healthy recombinase activating gene (Rag)(-/)- T cell receptor (TCR) transgenic mice and nontransgenic mice even when the transgenic TCR is specific for a CNS antigen. Transgenic T cells isolated from the CNS that are specific for non-CNS antigens are phenotypically naive and proliferate robustly to antigenic stimulation in vitro. Strikingly, transgenic T cells isolated from the CNS that are specific for myelin basic protein (MBP) are also primarily phenotypically naive but are unresponsive to antigenic stimulation in vitro. Mononuclear cells from the CNS of MBP TCR transgenic but not nontransgenic mice can suppress the response of peripheral MBP-specific T cells in vitro. These results indicate that naive MBP-specific T cells can traffic to the CNS but do not trigger autoimmunity because they undergo tolerance induction in situ.

Show MeSH
Related in: MedlinePlus