上海士鋒生物TCR親和力和負(fù)性調(diào)節(jié)限制了自身免疫

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TCR affinity and negative regulation limit autoimmunity

Matthew A Gronski¹, Jonathan M Boulter², Demetrius Moskophidis³, Linh T Nguyen¹, Kaisa Holmberg⁴, Alisha R Elford¹, Elissa K Deenick¹, Hee O Kim⁴, Josef M Penninger⁵, Bernhard Odermatt⁶, Awen Gallimore², Nicholas R J Gascoigne⁴ & Pamela S Ohashi¹

Autoimmune diseases are often mediated by self-reactive T cells, which must be activated to cause immunopathology. One mechanism, known as molecular mimicry, proposes that self-reactive T cells may be activated by pathogens expressing crossreactive ligands^{1, 2, 3}. Here we have developed a model to investigate how the affinity of the T-cell receptor （TCR） for the activating agent influences autoimmunity. Our model shows that an approximay fivefold difference in the TCR affinity for the activating ligand results in a 50% reduction in the incidence of autoimmunity. A reduction in TCR-ligand affinity to approximay 20 times lower than normal does not induce autoimmunity despite the unexpected induction of cytotoxic T lymphocytes （CTLs） and insulitis. Furthermore, in the absence of a key negative regulatory molecule, Cbl-b^{4, 5}, 100% of mice develop autoimmunity upon infection with viruses encoding the lower-affinity ligand. Therefore, autoimmune disease is sensitive both to the affinity of the activating ligand and to normal mechanisms that negatively regulate the immune response.

Figure 1. Characterizing P14 T-cell responses to variant viruses.

（a–c） Binding of soluble P14 TCR to （a） H-2D^b gp33 （b） H-2D^b L6F and （c） H-2D^b C4Y. H-2D^b-HY （to which the P14 TCR does not bind） was used as a control. （d） Expression of cell-surface markers V2, CD44, LFA-1 （CD11a）, CD49d and CD62L on CD8⁺ T cells from P14 TCR transgenic mice that were immunized with wild-type LCMV, LCMV-L6F, LCMV-C4Y or vaccinia virus or were left uninfected. Profiles are shown from gated CD8⁺ populations. The values indicated are median fluorescence intensities. Representative data from six mice per treatment. （e） CTL activity from wild-type LCMV-, LCMV-L6F- or LCMV-C4Y-infected P14 transgenic mice was assessed on gp33-pulsed EL4 target cells. Lysis of negative control AV target peptide–pulsed cells was <5%. E/T ratio, effector/target ratio. （f） Percentage of CD8⁺V2⁺ T cells of the total CD8⁺ population, determined by flow cytometry

Figure 2. Limited induction of diabetes by the LCMV-L6F variant virus despite effective ex vivo CTL function and islet infiltration.

（a–c） Diabetes （left panels） and insulitis （right panels） as assessed by immunohistochemistry for CD8⁺ infiltrates （stained red） in P14/RIP-gp mice that were immunized with （a） wild-type LCMV （b） LCMV-L6F （c） LCMV-C4Y. Each line depicts blood glucose of a single mouse. （d） Islets from P14 single-transgenic mice infected with wild-type LCMV. Representative profiles are shown. （e） Summary of the immunohistochemistry results for CD8⁺ infiltration of the islets. Results are from at least 6 mice and 20 islets per group.

Figure 3. Effective CTL induction by the LCMV-L6F variant virus with limited diabetes.

（a,b） Lysis of gp33 peptide–pulsed EL4 target cells by splenocytes from C57Bl/6 mice infected with （a） wild-type LCMV or （b） LCMV-L6F 8 d earlier. E/T ratio, effector/target ratio. Each line depicts CTL activity from an individual mouse （n = 6）. （c,d） RIP-gp mice were infected with （c） wild-type LCMV or （d） LCMV-L6F and the onset of diabetes （left panels） and day 8 CD8⁺ T cell infiltration （right panels） were monitored. In c, n = 7; in d, n = 10. Symbols distinguish individual mice. （e） Pancreatic sections from uninfected RIP-gp mice are shown.

Figure 4. Diabetes induction in RIP-gp mice is limited by Cbl-b.

（a） Diabetes induction in RIP-gp Cblb^-/- mice that were infected with LCMV-L6F. （b） In vivo proliferation, evaluated as percentage of CD8⁺V2⁺ cells of the total CD8⁺ population 7 d after infection as compared to uninfected control animals. （c,d） Diabetes in （c） RIP-gp Cblb^-/- or （d） RIP-gp Cblb^+/+ mice after wild-type LCMV infection. （e） CTL induction in Cblb^+/+ and Cblb^-/- mice 8 d after LCMV-L6F immunization. Each line represents one mouse. （f） Summary of CD8⁺ T-cell infiltration into the islets in RIP-gp Cblb^+/+ and RIP-gp Cblb^-/- on days 6, 8 and 15 after LCMV-L6F infection. Symbols represent individual mice from the same group and treatment.

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