Aiko Kato

Physiologic Thymic Involution Underlies Age-Dependent Accumulation of Senescence-Associated CD4+ T Cells

Immune aging may underlie various aging-related disorders, including diminished resistance to infection, chronic inflammatory disorders, and autoimmunity. PD-1+ and CD153+ CD44high CD4+ T cells with features of cellular senescence, termed senescence-associated T (SA-T) cells, increasingly accumulate with age and may play a role in the immune aging phenotype. In this article, we demonstrate that, compared with young mice, the aged mouse environment is highly permissive for spontaneous proliferation of transferred naive CD4+ T cells, and it drives their transition to PD-1+ and CD153+ CD44high CD4+ T cells after extensive cell divisions. CD4+ T cells with essentially the same features as SA-T cells in aged mice are also generated from naive CD4+ T cells after extensive cell divisions under severe T-lymphopenic conditions by gamma irradiation or in developmental T cell defect, often in association with spontaneous germinal centers, as seen in aged mice. The increase in SA-T cells is significantly enhanced after thymectomy at the young adult stage, along with accelerated T cell homeostatic proliferation, whereas embryonic thymus implantation in the late adult stage markedly restricts the homeostatic proliferation of naive CD4+ T cells in the host and delays the increase in SA-T cells. Our results suggest that reduced T cell output due to physiologic thymic involution underlies the age-dependent accumulation of SA-T cells as a result of increasing homeostatic proliferation of naive CD4+ T cells. SA-T cells may provide a suitable biomarker of immune aging, as well as a potential target for controlling aging-related disorders.

Human herpes virus 6-associated myelitis following allogeneic bone marrow transplantation

Dear Editor,Human herpes virus 6 (HHV6) can be reactivated in recip-ients of hematopoietic stem cell transplantation (HSCT),resulting in a number of clinical manifestations [1].HHV6-associated myelitis is characterized by dysesthesiaof the lower extremities, dysuria, or dyschezia, without anysymptoms of encephalitis [2, 3]. All previously reportedcases of HHV6-associated myelitis occurred in cord bloodtransplantation (CBT) recipients [2, 3]. Here, we report acase of HHV6-associated myelitis developed in a bonemarrow transplantation (BMT) recipient.A 20-year-old Japanese male with Philadelphia-negativeacute lymphoblastic leukemia received myeloablativeallogeneic BMT from a human leukocyte antigen-DRallele single mismatched unrelated donor during a secondremission (Fig. 1). A total of 2.08×10

HIV-related NK/T-cell lymphoma in the brain relapsed during intensive chemotherapy but regressed after chemotherapy discontinuation: the importance of maintaining cellular immunity.

This study reports a case of human immunodeficiency virus (HIV)-related natural killer/T-cell lymphoma with an unexpected clinical course. The lymphoma cells were positive for Epstein–Barr virus and the primary nodal lesions regressed after chemotherapy and combined antiretroviral therapy (c-ART); however, brain metastasis progressed along with a reduction in the CD8+ T-cell count. Chemotherapy was discontinued and the patient was treated with c-ART alone, resulting in regression of the brain lesions and recovery of the CD8+ T-cell count. This case highlights the importance of maintaining anti-tumor immunity in patients with HIV-related lymphoma.

CXCR3high CD8+ T cells with naïve phenotype and high capacity for IFN-γ production are generated during homeostatic T-cell proliferation

Naïve phenotype (NP) T cells spontaneously initiate homeostatic proliferation (HP) as T‐cell output is reduced because of physiologic thymic involution with age. However, the effects of sustained HP on overall immune function are poorly understood. We demonstrated that the NP CD8+ T cell population in adult thymectomized mice showing accelerated HP has an increased capacity for TCR‐mediated interferon‐γ and tumor necrosis factor α production, which is attributed to an increase in CXCR3+ cells in the NP CD8+ T cell population. The CXCR3+ NP CD8+ T cells developed during persistent HP with a slow cell division rate, but rarely during robust antigen‐driven proliferation with a fast cell division rate. In ontogeny, the proportions of CXCR3+ cells in the NP CD8+ T cell population showed a biphasic profile, which was high at the newborn and aged stages. Upon transfer, CXCR3+ NP CD8+ T cells, but not CXCR3− NP CD8+ T cells, potently enhanced Th17‐mediated inflammatory tissue reactions in vivo. Furthermore, CXCR3high NP CD8+ T cells with similar features were also detected at variable levels in healthy human blood. These results suggest that CXCR3+ NP CD8+ T cells generated during physiological HP significantly impact overall immunity at the immunologically vulnerable neonatal and aged stages.