生物谷報道：自身免疫一直是免疫學(xué)研究的熱點,，但是自身免疫到底與TCR關(guān)系如何？一直沒有清晰的答案,，這篇研究提供了一個清晰的線圖,。

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 ligands1, 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 approximately 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 approximately 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-b4, 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-2Db gp33 (b) H-2Db L6F and (c) H-2Db C4Y. H-2Db-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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