Gail Daniel P, Suzart Vinicius G, Du Weinan, Kaur Sandhu Avinaash, Jarvela Jessica, Nantongo Mary, Mwebaza Ivan, Panigrahi Soumya, Freeman Michael L, Canaday David H, Boom W Henry, Silver Richard F, Carpenter Stephen M
Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Biomedical Sciences Training Program, Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
iScience. 2023 Aug 23;26(9):107706. doi: 10.1016/j.isci.2023.107706. eCollection 2023 Sep 15.
Direct recognition of (Mtb)-infected cells is required for protection by CD4 T cells. While impaired T cell recognition of Mtb-infected macrophages was demonstrated in mice, data are lacking for humans. Using T cells and monocyte-derived macrophages (MDMs) from individuals with latent Mtb infection (LTBI), we quantified the frequency of memory CD4 T cell activation in response to autologous MDMs infected with virulent Mtb. We observed robust T cell activation in response to Mtb infection of M1-like macrophages differentiated using GM-CSF, while M2-like macrophages differentiated using M-CSF were poorly recognized. However, non-infected GM-CSF and M-CSF MDMs loaded with exogenous antigens elicited similar CD4 T cell activation. IL-10 was preferentially secreted by infected M-CSF MDMs, and neutralization improved T cell activation. These results suggest that preferential infection of macrophages with an M2-like phenotype limits T cell-mediated protection against Mtb. Vaccine development should focus on T cell recognition of Mtb-infected macrophages.
CD4 T细胞发挥保护作用需要直接识别被结核分枝杆菌（Mtb）感染的细胞。虽然在小鼠中已证实T细胞对感染Mtb的巨噬细胞的识别受损，但人类相关数据尚缺。我们利用来自潜伏性结核分枝杆菌感染（LTBI）个体的T细胞和单核细胞衍生的巨噬细胞（MDM），量化了记忆性CD4 T细胞对感染强毒Mtb的自体MDM作出反应时的激活频率。我们观察到，使用GM-CSF分化的M1样巨噬细胞感染Mtb后可引发强烈的T细胞激活，而使用M-CSF分化的M2样巨噬细胞则很难被识别。然而，负载外源性抗原的未感染GM-CSF和M-CSF MDM可引发相似的CD4 T细胞激活。感染的M-CSF MDM优先分泌IL-10，中和IL-10可改善T细胞激活。这些结果表明，具有M2样表型的巨噬细胞被优先感染会限制T细胞介导的抗Mtb保护作用。疫苗研发应聚焦于T细胞对感染Mtb的巨噬细胞的识别。
