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B cells and T cells collaborate in multiple sclerosis (MS) pathogenesis. IgH[MOG] mice possess a B cell repertoire skewed to recognize myelin oligodendrocyte glycoprotein (MOG). Here, we show that upon immunization with the T cell-obligate autoantigen, MOG[35-55], IgH[MOG] mice develop rapid and exacerbated experimental autoimmune encephalomyelitis (EAE) relative to wildtype (WT) counterparts, characterized by aggregation of T and B cells in the IgH[MOG] meninges and by CD4+ T helper 17 (Th17) cells in the CNS. Production of the Th17 maintenance factor IL-23 is observed from IgH[MOG] CNS-infiltrating and meningeal B cells, and in vivo blockade of IL-23p19 attenuates disease severity in IgH[MOG] mice. In the CNS parenchyma and dura mater of IgH[MOG] mice, we observe an increased frequency of CD4+PD-1+CXCR5- T cells that share numerous characteristics with the recently described T peripheral helper (Tph) cell subset. Further, CNS-infiltrating B and Tph cells from IgH[MOG] mice show increased reactive oxygen species (ROS) production. Meningeal inflammation, Tph-like cell accumulation in the CNS and B/Tph cell production of ROS were all reduced upon p19 blockade. Altogether, MOG-specific B cells promote autoimmune inflammation of the CNS parenchyma and meninges in an IL-23-dependent manner. B cells are crucial in multiple sclerosis (MS) pathology but the mechanisms are incompletely understood. In a mouse model of MS, the authors show that B cells make IL-23, and that IL-23 invokes meningeal inflammation and CNS presence of T peripheral helper cells. [ABSTRACT FROM AUTHOR]

Antiretroviral therapy (ART) effectively extends the life expectancy of human immunodeficiency virus (HIV)-infected individuals; however, agerelated morbidities have emerged as major clinical concerns. In this context, coinfection with cytomegalovirus (CMV) accelerates immune senescence and elevates risk for other agerelated morbidities, possibly through increased inflammation. We investigated potential relationships between CMV memory inflation, immune senescence, and inflammation by measuring markers of inflammation and telomere lengths of different lymphocyte subsets in HIVinfected individuals seropositive for antiCMV antibodies. Our study cohort consists mainly of middle aged men who have sex with men (MSM) and heterosexuals who are stable under longterm ART. Median levels of IL6, TNFα, and CRP were significantly higher in those coinfected with CMV. Lymphocyte telomere length in general correlated with age, but for 32/32 subjects tested, there was a consistent hierarchy of telomere lengths with CD8+ T cells' shorter than the general lymphocyte population, CD57+CD8+ T cells' shorter than CD8+ T cells' and CMVspecific CD57+CD8+ T cells' the shortest of all. Telomeres of HIVspecific CD8+ T cells were longer than those of CMVspecific CD8+ T cells in all cases tested and over 10 years, CMV-specific CD8+ T cell telomeres of two HIVinfected individuals eroded faster than those of HIVspecific CD8+ T cells. These data indicate that CMVspecific CD8+ T cells of HIVinfected individuals are the lymphocytes closest to telomereimposed replicative senescence. Exhaustive proliferation of CMVspecific CD8+ T cells in HIVinfected individuals is a potential source of senescent lymphocytes affecting systemic immune function and inflammation. [ABSTRACT FROM AUTHOR]

Objective. Measuring NKG2C(+)CD57(+) natural killer (NK) cell expansion to investigate NK responses against human cytomegalovirus (HCMV) and assessing relationships with adaptive immunity against HCMV. Methods. Expansion of NKG2C(+)CD57(+) NK was measured in peripheral blood mononuclear cells (PBMC) from groups distinguished by HCMV and human immunodeficiency virus (HIV) infection status. Anti-HCMV antibody levels against HCMV-infected MRC-5 cell lysate were assessed by ELISA and HCMV-specific CD8(+) T cell responses characterized by intracellular flow cytometry following PBMC stimulation with immunodominant HCMV peptides. Results. Median NK, antibody, and CD8(+) T cell responses against HCMV were significantly greater in the HCMV/HIV coinfected group than the group infected with CMV alone. The fraction of CMV-specific CD8(+) T cells expressing CD28 correlated inversely with NKG2C(+)CD57(+) NK expansion in HIV infection. Conclusion. Our data reveal no significant direct relationships between NK and adaptive immunity against HCMV. However, stronger NK and adaptive immune responses against HCMV and an inverse correlation between NKG2C(+)CD57(+) NK expansion and proliferative reserve of HCMV-specific CD8(+) T cells, as signified by CD28 expression, indicate parallel evolution of NK and T cell responses against HCMV in HIV infection. Similar aspects of chronic HCMV infection may drive both NK and CD8(+) T cell memory inflation. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "CD8 T-cell expansion and inflammation linked to CMV coinfection in ART-treated HIV infection" in the 2016 issue.

Expansion of natural killer (NK) cells expressing NKG2C occurs following human cytomegalovirus (HCMV) infection and is amplified by human immunodeficiency virus (HIV) co-infection. These NKG2C-expressing NK cells demonstrate enhanced CD16-dependent cytokine production and downregulate FcεRIγ and promyelocytic leukemia zinc finger protein (PLZF). Lacking NKG2C diminishes resistance to HIV infection, but whether this affects NK cell acquisition of superior antibody-dependent function is unclear. Therefore, our objective was to investigate whether HCMV-driven NK cell differentiation is impaired in NKG2C null HIV-infected individuals. Phenotypic (CD2, CD16, CD57, NKG2A, FcεRIγ, and PLZF expression) and functional (cytokine induction and cytotoxicity) properties were compared between HIV⁻infected NKG2C null and NKG2C-expressing groups. Cytokine production was compared following stimulation through natural cytotoxicity receptors or through CD16. Cytotoxicity was measured by anti-CD16-redirected lysis and by classical antibody-dependent cell-mediated cytotoxicity (ADCC) against anti-class I human leukocyte antigen (HLA) antibody-coated cells. Our data indicate highly similar HCMV-driven NK cell differentiation in HIV infection with or without NKG2C. While the fraction of mature (CD57 pos ) NK cells expressing CD2 ( p = 0.009) or co-expressing CD2 and CD16 (p = 0.03) was significantly higher in NKG2C null HIV-infected individuals, there were no significant differences in NKG2A, FcεRIγ, or PLZF expression. The general phenotypic and functional equivalency observed suggests NKG2C-independent routes of HCMV-driven NK cell differentiation, which may involve increased CD2 expression .

Antiretroviral therapy (ART) effectively extends the life expectancy of human immunodeficiency virus (HIV)-infected individuals; however, age-related morbidities have emerged as major clinical concerns. In this context, coinfection with cytomegalovirus (CMV) accelerates immune senescence and elevates risk for other age-related morbidities, possibly through increased inflammation. We investigated potential relationships between CMV memory inflation, immune senescence, and inflammation by measuring markers of inflammation and telomere lengths of different lymphocyte subsets in HIV-infected individuals seropositive for anti-CMV antibodies. Our study cohort consists mainly of middle aged men who have sex with men (MSM) and heterosexuals who are stable under long-term ART. Median levels of IL-6, TNF-α, and CRP were significantly higher in those coinfected with CMV. Lymphocyte telomere length in general correlated with age, but for 32/32 subjects tested, there was a consistent hierarchy of telomere lengths with CD8 + T cells' shorter than the general lymphocyte population, CD57 + CD8 + T cells' shorter than CD8 + T cells' and CMV-specific CD57 + CD8 + T cells' the shortest of all. Telomeres of HIV-specific CD8 + T cells were longer than those of CMV-specific CD8 + T cells in all cases tested and over 10 years, CMV-specific CD8 + T cell telomeres of two HIV-infected individuals eroded faster than those of HIV-specific CD8 + T cells. These data indicate that CMV-specific CD8 + T cells of HIV-infected individuals are the lymphocytes closest to telomere-imposed replicative senescence. Exhaustive proliferation of CMV-specific CD8 + T cells in HIV-infected individuals is a potential source of senescent lymphocytes affecting systemic immune function and inflammation.