干扰素调节因子 8 (IRF8) 突变导致淋巴瘤发生的机制尚不清楚。我们对 B 细胞淋巴瘤中的 IRF8 变异进行建模，发现它们影响抗原呈递调节因子的表达。 IRF8突变体在鼠B细胞淋巴瘤中的表达抑制CD4，但不抑制CD8，抗原呈递引起的激活和下调CD74和人白细胞抗原（HLA）DM，主要组织相容性复合体（MHC）II中抗原肽加工/加载的细胞内调节因子。一致地，突变型IRF8与这些基因的启动子的结合效率较低。携带IRF8突变淋巴瘤的小鼠表现出更高的肿瘤负荷和肿瘤微环境的重塑，其典型特征是CD4、CD8和自然杀伤细胞的消耗，调节性T细胞和滤泡辅助T细胞的增加。对 IRF8 突变型人弥漫性大 B 细胞淋巴瘤 (DLBCL) 的大量 RNA 测序数据进行解卷积，重现了在小鼠中检测到的部分免疫重塑。我们得出的结论是，IRF8 突变通过促进免疫逃逸而促进 DLBCL 生物学。

The mechanism by which interferon regulatory factor 8 (IRF8) mutation contributes to lymphomagenesis is unknown. We modeled IRF8 variants in B cell lymphomas and found that they affected the expression of regulators of antigen presentation. Expression of IRF8 mutants in murine B cell lymphomas suppressed CD4, but not CD8, activation elicited by antigen presentation and downmodulated CD74 and human leukocyte antigen (HLA) DM, intracellular regulators of antigen peptide processing/loading in the major histocompatibility complex (MHC) II. Concordantly, mutant IRF8 bound less efficiently to the promoters of these genes. Mice harboring IRF8 mutant lymphomas displayed higher tumor burden and remodeling of the tumor microenvironment, typified by depletion of CD4, CD8, and natural killer cells, increase in regulatory T cells and T follicular helper cells. Deconvolution of bulk RNA sequencing data from IRF8-mutant human diffuse large B cell lymphoma (DLBCL) recapitulated part of the immune remodeling detected in mice. We concluded that IRF8 mutations contribute to DLBCL biology by facilitating immune escape.