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Myelin basic protein-specific T helper 2 (Th2) cells cause experimental autoimmune encephalomyelitis in immunodeficient hosts rather than protect them from the disease.

Lafaille JJ, Keere FV, Hsu AL, Baron JL, Haas W, Raine CS, Tonegawa S - J. Exp. Med. (1997)

Bottom Line: The histopathological features of this disease resembled those of an allergic process.In addition, disease induction by Th1 cells was not altered by coadmininstration of Th2 cells in any of the recipients.These findings indicate that MBP-specific Th2 cells have the potential to induce EAE and that the disease induced by previously activated Th1 cells cannot be prevented by normal lymphocytes nor by previously activated Th2 cells.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, Center for Cancer Research, and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

ABSTRACT
Chronic inflammatory autoimmune diseases such as multiple sclerosis, diabetes, and rheumatoid arthritis are caused by CD4(+) Th1 cells. Because Th2 cells antagonize Th1 cell functions in several ways, it is believed that immune deviation towards Th2 can prevent or cure autoimmune diseases. Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease used as a model for multiple sclerosis. Using an adoptive transfer system we assessed the role of Th1 and Th2 cells in EAE. In vitro generated Th1 and Th2 cells from myelin basic protein (MBP)-specific TCR transgenic mice were transferred into normal and immunodeficient mice. Th1 cells caused EAE in all recipients after a brief preclinical phase. Surprisingly, Th2 cells also caused EAE in RAG-1 KO mice and in alphabeta T cell-deficient mice, albeit after a longer preclinical phase. Normal or gammadelta T cell-deficient mice were resistant to EAE induced by Th2 cells. The histopathological features of this disease resembled those of an allergic process. In addition, disease induction by Th1 cells was not altered by coadmininstration of Th2 cells in any of the recipients. These findings indicate that MBP-specific Th2 cells have the potential to induce EAE and that the disease induced by previously activated Th1 cells cannot be prevented by normal lymphocytes nor by previously activated Th2 cells.

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Th2 cells but not  Th1 cells are recovered from animals to which cells from Th2  cell cultures had been injected.  Spleen (top two panels) and CNS  cells from mice injected with  Th2 cells were prepared 40 d after injection, when mice were at  level 2 and 3 of EAE. The lower  two panels show purified CD4-positive cells. RT-PCR was performed to determine mRNA  levels of IL-4, IFN-γ, and IL-10.  The IFN-γ mRNA present in  total splenocytes and absent in  CD4 purified splenocytes and  lymphocytes from CNS is likely  coming from NK cells.
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Figure 2: Th2 cells but not Th1 cells are recovered from animals to which cells from Th2 cell cultures had been injected. Spleen (top two panels) and CNS cells from mice injected with Th2 cells were prepared 40 d after injection, when mice were at level 2 and 3 of EAE. The lower two panels show purified CD4-positive cells. RT-PCR was performed to determine mRNA levels of IL-4, IFN-γ, and IL-10. The IFN-γ mRNA present in total splenocytes and absent in CD4 purified splenocytes and lymphocytes from CNS is likely coming from NK cells.

Mentions: Since disease induction by Th2 cells was unexpected, we considered the possibility that the Th2 cell population contained some Th1 cells which were responsible for the delayed onset of signs. If this was the case, injection of low doses of Th1 cells should mimic the kinetics and final incidence of EAE observed upon injection of a high number of Th2 cells. However, this was not the case. Disease incidence fell with decreasing numbers of transferred Th1 or Th2 cells; however, the final incidence was comparable for recipients of either Th1 or Th2 cells (Fig. 1 B). Thus, a small number of contaminant Th1 cells does not explain the high incidence of EAE in recipients of 5 × 106 Th2 cells. We also considered the possibility that some Th2 cells were converted in vivo into Th1 cells. No evidence for such a conversion was obtained when cytokine mRNA was analyzed in extracts of spleens and brains of Th2 cell recipients which developed the disease: CD4+ T cells that were isolated from spleen and brain of Th2 cell recipients were found to produce IL-4 mRNA but not IFN-γ mRNA (Fig. 2). Moreover, we assessed whether we could convert in vitro the three times-stimulated Th2 cells into a Th1 phenotype by adding IL-12 or IFN-γ and observed no conversion, thereby confirming previous findings (21– 23 and data not shown).


Myelin basic protein-specific T helper 2 (Th2) cells cause experimental autoimmune encephalomyelitis in immunodeficient hosts rather than protect them from the disease.

Lafaille JJ, Keere FV, Hsu AL, Baron JL, Haas W, Raine CS, Tonegawa S - J. Exp. Med. (1997)

Th2 cells but not  Th1 cells are recovered from animals to which cells from Th2  cell cultures had been injected.  Spleen (top two panels) and CNS  cells from mice injected with  Th2 cells were prepared 40 d after injection, when mice were at  level 2 and 3 of EAE. The lower  two panels show purified CD4-positive cells. RT-PCR was performed to determine mRNA  levels of IL-4, IFN-γ, and IL-10.  The IFN-γ mRNA present in  total splenocytes and absent in  CD4 purified splenocytes and  lymphocytes from CNS is likely  coming from NK cells.
© Copyright Policy
Related In: Results  -  Collection

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Figure 2: Th2 cells but not Th1 cells are recovered from animals to which cells from Th2 cell cultures had been injected. Spleen (top two panels) and CNS cells from mice injected with Th2 cells were prepared 40 d after injection, when mice were at level 2 and 3 of EAE. The lower two panels show purified CD4-positive cells. RT-PCR was performed to determine mRNA levels of IL-4, IFN-γ, and IL-10. The IFN-γ mRNA present in total splenocytes and absent in CD4 purified splenocytes and lymphocytes from CNS is likely coming from NK cells.
Mentions: Since disease induction by Th2 cells was unexpected, we considered the possibility that the Th2 cell population contained some Th1 cells which were responsible for the delayed onset of signs. If this was the case, injection of low doses of Th1 cells should mimic the kinetics and final incidence of EAE observed upon injection of a high number of Th2 cells. However, this was not the case. Disease incidence fell with decreasing numbers of transferred Th1 or Th2 cells; however, the final incidence was comparable for recipients of either Th1 or Th2 cells (Fig. 1 B). Thus, a small number of contaminant Th1 cells does not explain the high incidence of EAE in recipients of 5 × 106 Th2 cells. We also considered the possibility that some Th2 cells were converted in vivo into Th1 cells. No evidence for such a conversion was obtained when cytokine mRNA was analyzed in extracts of spleens and brains of Th2 cell recipients which developed the disease: CD4+ T cells that were isolated from spleen and brain of Th2 cell recipients were found to produce IL-4 mRNA but not IFN-γ mRNA (Fig. 2). Moreover, we assessed whether we could convert in vitro the three times-stimulated Th2 cells into a Th1 phenotype by adding IL-12 or IFN-γ and observed no conversion, thereby confirming previous findings (21– 23 and data not shown).

Bottom Line: The histopathological features of this disease resembled those of an allergic process.In addition, disease induction by Th1 cells was not altered by coadmininstration of Th2 cells in any of the recipients.These findings indicate that MBP-specific Th2 cells have the potential to induce EAE and that the disease induced by previously activated Th1 cells cannot be prevented by normal lymphocytes nor by previously activated Th2 cells.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, Center for Cancer Research, and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

ABSTRACT
Chronic inflammatory autoimmune diseases such as multiple sclerosis, diabetes, and rheumatoid arthritis are caused by CD4(+) Th1 cells. Because Th2 cells antagonize Th1 cell functions in several ways, it is believed that immune deviation towards Th2 can prevent or cure autoimmune diseases. Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease used as a model for multiple sclerosis. Using an adoptive transfer system we assessed the role of Th1 and Th2 cells in EAE. In vitro generated Th1 and Th2 cells from myelin basic protein (MBP)-specific TCR transgenic mice were transferred into normal and immunodeficient mice. Th1 cells caused EAE in all recipients after a brief preclinical phase. Surprisingly, Th2 cells also caused EAE in RAG-1 KO mice and in alphabeta T cell-deficient mice, albeit after a longer preclinical phase. Normal or gammadelta T cell-deficient mice were resistant to EAE induced by Th2 cells. The histopathological features of this disease resembled those of an allergic process. In addition, disease induction by Th1 cells was not altered by coadmininstration of Th2 cells in any of the recipients. These findings indicate that MBP-specific Th2 cells have the potential to induce EAE and that the disease induced by previously activated Th1 cells cannot be prevented by normal lymphocytes nor by previously activated Th2 cells.

Show MeSH
Related in: MedlinePlus