Levin Ditza, DiPaolo Richard J, Brinster Carine, Revilleza Maria Jamela R, Boyd Lisa F, Teyton Luc, Natarajan Kannan, Mage Michael G, Shevach Ethan M, Margulies David H
Department of Biotechnology Engineering, Ort Braude College, Karmiel, Israel.
Eur J Immunol. 2008 Dec;38(12):3339-53. doi: 10.1002/eji.200838584.
We examined TCR:MHC/peptide interactions and in vivo epitope availability to explore the Th1- or Th2-like phenotype of autoimmune disease in two TCR Tg mouse models of autoimmune gastritis (AIG). The TCR of strains A23 and A51 recognize distinct IA(d)-restricted peptides from the gastric parietal cell H/K-ATPase. Both peptides form extremely stable MHC/peptide (MHC/p) complexes. All A23 animals develop a Th1-like aggressive, inflammatory AIG early in life, while A51 mice develop indolent Th2-like AIG at 6-8 wk with incomplete penetrance. A51 T cells were more sensitive than A23 to low doses of soluble antigen and to MHC/p complexes. Staining with IA(d)/peptide tetramers was only detectable on previously activated T cells from A51. Thus, despite inducing a milder AIG, the A51 TCR displays a higher avidity for its cognate IA(d)/peptide. Nonetheless, in vivo proliferation of adoptively transferred A51 CFSE-labeled T cells in the gastric lymph node was relatively poor compared with A23 T cells. Also, DC from WT gastric lymph node, presenting processed antigen available in vivo, stimulated proliferation of A23 T cells better than A51. Thus, the autoimmune potential of these TCR in their respective Tg lines is strongly influenced by the availability of the peptide epitope, rather than by differential avidity for their respective MHC/p complexes.
我们检测了TCR:MHC/肽相互作用以及体内表位可用性，以探究两种自身免疫性胃炎（AIG）TCR转基因小鼠模型中自身免疫疾病的Th1样或Th2样表型。A23和A51品系的TCR识别来自胃壁细胞H/K-ATP酶的不同IA(d)限制性肽。两种肽均形成极其稳定的MHC/肽（MHC/p）复合物。所有A23动物在生命早期就会发展出类似Th1的侵袭性炎症性AIG，而A51小鼠在6-8周时会发展出不明显的类似Th2的AIG，且发病率不完全。A51 T细胞比A23 T细胞对低剂量可溶性抗原和MHC/p复合物更敏感。仅在来自A51的先前活化的T细胞上可检测到用IA(d)/肽四聚体染色。因此，尽管诱导的AIG较轻，但A51 TCR对其同源IA(d)/肽表现出更高的亲和力。尽管如此，与A23 T细胞相比，过继转移的A51 CFSE标记的T细胞在胃淋巴结中的体内增殖相对较差。此外，来自野生型胃淋巴结的DC呈递体内可用的加工抗原，其刺激A23 T细胞增殖的能力优于A51。因此，这些TCR在各自转基因系中的自身免疫潜力受肽表位可用性的强烈影响，而非受其对各自MHC/p复合物的不同亲和力的影响。
