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Autopathogenic T helper cell type 1 (Th1) and protective Th2 clones differ in their recognition of the autoantigenic peptide of myelin proteolipid protein.

Das MP, Nicholson LB, Greer JM, Kuchroo VK - J. Exp. Med. (1997)

Bottom Line: These Th2 cells do not show any dependence on the W144, but show a critical requirement for L141/G142 as their major TCR contact residue.Thus, in contrast with the Th1 clones that did not proliferate to A144-substituted peptide, the Th2 clones tolerated a substitution at position 144 and proliferated to A144 peptide.These data suggest that a balance between two different T cell repertoires specific for same autoantigenic epitope can determine disease phenotype, i.e., resistance or susceptibility to an autoimmune disease.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

ABSTRACT
We previously generated a panel of T helper cell 1 (Th1) clones specific for an encephalitogenic peptide of myelin proteolipid protein (PLP) peptide 139-151 (HSLGKWLGHPDKF) that induces experimental autoimmune encephalomyelitis (EAE) upon adoptive transfer. In spite of the differences in their T cell receptor (TCR) gene usage, all these Th1 clones required W144 as the primary and most critical TCR contact residue for the activation. In this study, we determined the TCR contact residues of a panel of Th2/Th0 clones specific for the PLP peptide 139-151 generated either by immunization with the PLP 139-151 peptide with anti- B7-1 antibody or by immunization with an altered peptide Q144. Using alanine-substituted peptide analogues of the native PLP peptide, we show that the Th2 clones have shifted their primary contact residue to the NH2-terminal end of the peptide. These Th2 cells do not show any dependence on the W144, but show a critical requirement for L141/G142 as their major TCR contact residue. Thus, in contrast with the Th1 clones that did not proliferate to A144-substituted peptide, the Th2 clones tolerated a substitution at position 144 and proliferated to A144 peptide. This alternative A144 reactive repertoire appears to have a critical role in the regulation of autoimmune response to PLP 139-151 because preimmunization with A144 to expand the L141/G142-reactive repertoire protects mice from developing EAE induced with the native PLP 139-151 peptide. These data suggest that a balance between two different T cell repertoires specific for same autoantigenic epitope can determine disease phenotype, i.e., resistance or susceptibility to an autoimmune disease.

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Proliferative response of lymph node cells of SJL mice immunized with 100 μg/mouse of PLP 139–151, A144, or a mixture of  PLP 139–151 plus A144 peptides in CFA. Lymph node cells were activated 10 d after immunization with indicated peptides in a 3-d proliferation assay. Data represent mean CPM in triplicate wells.
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Figure 5: Proliferative response of lymph node cells of SJL mice immunized with 100 μg/mouse of PLP 139–151, A144, or a mixture of PLP 139–151 plus A144 peptides in CFA. Lymph node cells were activated 10 d after immunization with indicated peptides in a 3-d proliferation assay. Data represent mean CPM in triplicate wells.

Mentions: Besides expanding a protective T cell repertoire, several other mechanisms could explain protective effects of preimmunization with A144 peptide; for example, A144 could mediate MHC blockade or antagonize PLP 139–151-specific Th1 cells and inhibit generation of an encephalitogenic T cell repertoire. A144 peptide does not have significantly higher binding for I-As than the native PLP 139–151 peptide. Furthermore, we coimmunized mice with A144 plus PLP 139–151 peptides and tested the lymph node cells for their ability to proliferate to PLP 139–151 and A144 peptides. Coimmunization of mice with A144 plus PLP 139– 151 does not inhibit the generation of PLP 139–151-specific W144-reactive T cells (Fig. 5), suggesting that A144 does not mediate MHC blockade, thereby inhibiting the generation of W144-reactive cells. We have undertaken a detailed analysis to test whether A144 can act as a TCR antagonist of the PLP 139–151-specific Th1 repertoire. Our studies showed that the A144 does not antagonize PLP 139–151-specific T cell clones or PLP 139–151-specific T cell lines (17). To study whether A144 immunization expanded the protective Th2/Th0 repertoire, we immunized SJL mice with PLP 139–151 or A144 in CFA and tested the lymph node cells from these mice for proliferation and cytokine production by in vitro activation with native PLP 139–151 and A144 peptide (Table 2). The lymph node cells from PLP 139–151 immunized mice proliferated specifically to the native peptide and produced large amounts of Th1 cytokines, particularly IL–2 and IFN-γ. Consistent with the Th1 clone data, PLP 139–151-immunized lymph node cells did not show a significant proliferation or produce significant cytokines in response to A144 peptide. In contrast, the lymph node cells from the A144-immunized mice proliferated equally well to both the A144 and PLP 139–151 peptides as has been detected with the Th2/Th0 clones. The lymph node cells from A144-immunized mice when activated with A144 produced little IFN-γ, but produced large amounts of IL-10. We could not detect significant amounts of IL-4 in the primary lymph node cultures after activation with A144, but small amounts of IL-4 were detected after activation with the native peptide. These data are consistent with the observation that in contrast with the native peptide that induces Th1 cells, immunization with A144 even in CFA activates the alternate PLP 139–151 cross-reactive Th2/Th0 repertoire, which may be responsible for protection against EAE. The data obtained with immunization with the A144 peptide are similar in many ways to those obtained with the Q144 peptide in which we have seen that preimmunization with Q144 protects mice for the development of EAE and lymph node cells of these mice produce IL-10 upon in vitro activation (21). However, after cloning these cells in vitro, IL-4–producing Th2 clones were uncovered (21). It is relatively difficult to detect IL-4 in primary lymph node cultures, which may be due to very low levels of IL-4, or to its consumption or inhibition by other cytokines.


Autopathogenic T helper cell type 1 (Th1) and protective Th2 clones differ in their recognition of the autoantigenic peptide of myelin proteolipid protein.

Das MP, Nicholson LB, Greer JM, Kuchroo VK - J. Exp. Med. (1997)

Proliferative response of lymph node cells of SJL mice immunized with 100 μg/mouse of PLP 139–151, A144, or a mixture of  PLP 139–151 plus A144 peptides in CFA. Lymph node cells were activated 10 d after immunization with indicated peptides in a 3-d proliferation assay. Data represent mean CPM in triplicate wells.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199041&req=5

Figure 5: Proliferative response of lymph node cells of SJL mice immunized with 100 μg/mouse of PLP 139–151, A144, or a mixture of PLP 139–151 plus A144 peptides in CFA. Lymph node cells were activated 10 d after immunization with indicated peptides in a 3-d proliferation assay. Data represent mean CPM in triplicate wells.
Mentions: Besides expanding a protective T cell repertoire, several other mechanisms could explain protective effects of preimmunization with A144 peptide; for example, A144 could mediate MHC blockade or antagonize PLP 139–151-specific Th1 cells and inhibit generation of an encephalitogenic T cell repertoire. A144 peptide does not have significantly higher binding for I-As than the native PLP 139–151 peptide. Furthermore, we coimmunized mice with A144 plus PLP 139–151 peptides and tested the lymph node cells for their ability to proliferate to PLP 139–151 and A144 peptides. Coimmunization of mice with A144 plus PLP 139– 151 does not inhibit the generation of PLP 139–151-specific W144-reactive T cells (Fig. 5), suggesting that A144 does not mediate MHC blockade, thereby inhibiting the generation of W144-reactive cells. We have undertaken a detailed analysis to test whether A144 can act as a TCR antagonist of the PLP 139–151-specific Th1 repertoire. Our studies showed that the A144 does not antagonize PLP 139–151-specific T cell clones or PLP 139–151-specific T cell lines (17). To study whether A144 immunization expanded the protective Th2/Th0 repertoire, we immunized SJL mice with PLP 139–151 or A144 in CFA and tested the lymph node cells from these mice for proliferation and cytokine production by in vitro activation with native PLP 139–151 and A144 peptide (Table 2). The lymph node cells from PLP 139–151 immunized mice proliferated specifically to the native peptide and produced large amounts of Th1 cytokines, particularly IL–2 and IFN-γ. Consistent with the Th1 clone data, PLP 139–151-immunized lymph node cells did not show a significant proliferation or produce significant cytokines in response to A144 peptide. In contrast, the lymph node cells from the A144-immunized mice proliferated equally well to both the A144 and PLP 139–151 peptides as has been detected with the Th2/Th0 clones. The lymph node cells from A144-immunized mice when activated with A144 produced little IFN-γ, but produced large amounts of IL-10. We could not detect significant amounts of IL-4 in the primary lymph node cultures after activation with A144, but small amounts of IL-4 were detected after activation with the native peptide. These data are consistent with the observation that in contrast with the native peptide that induces Th1 cells, immunization with A144 even in CFA activates the alternate PLP 139–151 cross-reactive Th2/Th0 repertoire, which may be responsible for protection against EAE. The data obtained with immunization with the A144 peptide are similar in many ways to those obtained with the Q144 peptide in which we have seen that preimmunization with Q144 protects mice for the development of EAE and lymph node cells of these mice produce IL-10 upon in vitro activation (21). However, after cloning these cells in vitro, IL-4–producing Th2 clones were uncovered (21). It is relatively difficult to detect IL-4 in primary lymph node cultures, which may be due to very low levels of IL-4, or to its consumption or inhibition by other cytokines.

Bottom Line: These Th2 cells do not show any dependence on the W144, but show a critical requirement for L141/G142 as their major TCR contact residue.Thus, in contrast with the Th1 clones that did not proliferate to A144-substituted peptide, the Th2 clones tolerated a substitution at position 144 and proliferated to A144 peptide.These data suggest that a balance between two different T cell repertoires specific for same autoantigenic epitope can determine disease phenotype, i.e., resistance or susceptibility to an autoimmune disease.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

ABSTRACT
We previously generated a panel of T helper cell 1 (Th1) clones specific for an encephalitogenic peptide of myelin proteolipid protein (PLP) peptide 139-151 (HSLGKWLGHPDKF) that induces experimental autoimmune encephalomyelitis (EAE) upon adoptive transfer. In spite of the differences in their T cell receptor (TCR) gene usage, all these Th1 clones required W144 as the primary and most critical TCR contact residue for the activation. In this study, we determined the TCR contact residues of a panel of Th2/Th0 clones specific for the PLP peptide 139-151 generated either by immunization with the PLP 139-151 peptide with anti- B7-1 antibody or by immunization with an altered peptide Q144. Using alanine-substituted peptide analogues of the native PLP peptide, we show that the Th2 clones have shifted their primary contact residue to the NH2-terminal end of the peptide. These Th2 cells do not show any dependence on the W144, but show a critical requirement for L141/G142 as their major TCR contact residue. Thus, in contrast with the Th1 clones that did not proliferate to A144-substituted peptide, the Th2 clones tolerated a substitution at position 144 and proliferated to A144 peptide. This alternative A144 reactive repertoire appears to have a critical role in the regulation of autoimmune response to PLP 139-151 because preimmunization with A144 to expand the L141/G142-reactive repertoire protects mice from developing EAE induced with the native PLP 139-151 peptide. These data suggest that a balance between two different T cell repertoires specific for same autoantigenic epitope can determine disease phenotype, i.e., resistance or susceptibility to an autoimmune disease.

Show MeSH
Related in: MedlinePlus