木村 元子

To meet the energetic requirements associated with activation, proliferation and survival, T cells switch their metabolic signatures from energetically quiescent to activated. However, little is known about the role of metabolic pathway controlling the development of invariant natural killer T (iNKT) cells. In the present study, we found that acetyl-CoA carboxylase 1 (ACC1), a rate-limiting enzyme for fatty acid biosynthesis pathway, plays an essential role in the development of iNKT cells in the thymus. Mice lacking T-cell specific ACC1 showed reduced number of iNKT cells with an increased proportion of iNKT cells at immature stages 0 and 1. Furthermore, mixed bone marrow (BM) chimera experiments revealed that T-cell-intrinsic ACC1 expression was selectively important for the development of thymic iNKT cells, especially for the differentiation of NKT1 cell subset. Our single-cell RNA-sequencing (scRNA-seq) data and functional analysis demonstrated that ACC1 is responsible for survival of developing iNKT cells. Thus, these findings highlighted a novel role of ACC1 in controlling thymic iNKT cell development mediated by the control of cell survival.

Tumor-specific CD8+ T cells play a pivotal role in anti-tumor immunity and are a key target of immunotherapeutic approaches. Intratumoral CD8+ T cells are heterogeneous; Tcf1+ stem-like CD8+ T cells give rise to their cytotoxic progeny - Tim-3+ terminally differentiated CD8+ T cells. However, where and how this differentiation process occurs has not been elucidated. We herein show that terminally differentiated CD8+ T cells can be generated within tumor-draining lymph nodes (TDLNs) and that CD69 expression on tumor-specific CD8+ T cells controls its differentiation process through regulating the expression of the transcription factor TOX. In TDLNs, CD69 deficiency diminished TOX expression in tumor-specific CD8+ T cells, and consequently promoted generation of functional terminally differentiated CD8+ T cells. Anti-CD69 administration promoted the generation of terminally differentiated CD8+ T cells, and the combined use of anti-CD69 and anti-PD-1 showed an efficient anti-tumor effect. Thus, CD69 is an attractive target for cancer immunotherapy that synergizes with immune checkpoint blockade.

The mortality of coronavirus disease 2019 (COVID-19) is strongly correlated with pulmonary vascular pathology accompanied by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-triggered immune dysregulation and aberrant activation of platelets. We combined histological analyses using field emission scanning electron microscopy with energy-dispersive X-ray spectroscopy analyses of the lungs from autopsy samples and single-cell RNA sequencing of peripheral blood mononuclear cells to investigate the pathogenesis of vasculitis and immunothrombosis in COVID-19. We found that SARS-CoV-2 accumulated in the pulmonary vessels, causing exudative vasculitis accompanied by the emergence of thrombospondin-1-expressing noncanonical monocytes and the formation of myosin light chain 9 (Myl9)-containing microthrombi in the lung of COVID-19 patients with fatal disease. The amount of plasma Myl9 in COVID-19 was correlated with the clinical severity, and measuring plasma Myl9 together with other markers allowed us to predict the severity of the disease more accurately. This study provides detailed insight into the pathogenesis of vasculitis and immunothrombosis, which may lead to optimal medical treatment for COVID-19.

Regarding vascularized lymph node transfer (VLNT) for lymphedema, partial blood flow impairment in transferred lymph node (LN) flaps may adversely affect the therapeutic results. We investigated the clinical and histological effects of partial blood flow impairment in LN flaps. In upper extremity lymphedema cases, based on ultrasonographic examination at 2 weeks after VLNT, we compared the treatment results depending on whether the postoperative blood flow in transferred LNs was good (Group G) or poor (Group P). Novel partial ischemia and congestion of LN flap mouse models were developed to determine their histological features. In 42 cases, significant differences were observed between Group G (n = 37) and Group P (n = 5) based on the amount of volume reduction (136.7 ± 91.7 mL and 55.4 ± 60.4 mL, respectively; p = 0.04) and lymph flow recanalization rate in indocyanine green fluorescent lymphography (67.6% and 0%, respectively; p = 0.0007). In mouse models, thrombi formation in the marginal sinus and numerous Myl9/12-positive immunocompetent cells in follicles were observed in congested LNs. Blood flow maintenance in the transferred LNs is an essential factor influencing the therapeutic effect of VLNT. Postoperatively, surgeons should closely monitor blood flow in the transferred LNs, particularly in cases of congestion.