Influenza Virus Infection of Human Lymphocytes Occurs in the Immune Cell Cluster of the Developing Antiviral Response

Abstract

Monocytes-macrophages and lymphocytes are recruited to the respiratory tract in response to influenza virus challenge and are exposed to the virus during the establishment of immune defenses. The susceptibility of human lymphocytes to infection was assessed. The presence of monocytes-macrophages was required to attain infection of both resting and proliferating lymphocytes. Lymphocyte infection occurred in the context of immune cell clusters and was blocked by the addition of anti-intercellular adhesion molecule-1 (ICAM-1) antibody to prevent cell clustering. Both peripheral blood-derived and bronchoalveolar lymphocytes were susceptible to infection. Both CD4+ and CD8+ T lymphocytes were susceptible to influenza virus infection, and the infected CD4+ and CD8+ lymphocytes served as infectious foci for other nonpermissive or even virus-permissive cells. These data show that monocytes-macrophages and both CD4+ and CD8+ lymphocytes can become infected during the course of an immune response to influenza virus challenge. The described leukocyte interactions during infection may play an important role in the development of effective anti-influenza responses.

Diverse and Unexpected Roles of Human Monocytes/Macrophages in the Immune Response to Influenza Virus

“…Lymphocyte infection was decreased in a dose-dependent manner when anti-intercellular adhesion molecule-1 (ICAM-1) antibody was added to PBMC cultures to prevent clustering between monocytes/macrophages and lymphocytes. The studies also demonstrated that both peripheral blood lymphocytes and human alveolar lymphocytes required the presence of monocytes/macrophages for infection to occur [24]. Both CD4+ and CD8+ lymphocytes, and both resting and proliferating lymphocytes, became infected only when exposed to IAV in the presence of monocytes/macrophages.…”

“…Notably, the initiation of an immune response to IAV challenge involves the development of immune cell clusters between PBM and lymphocytes [23,24]. This challenge-induced structure provides the opportunity for PBM to act as accessory cells for the presentation of viral antigens to lymphocytes.…”

“…Further studies demonstrated that the immune cell cluster plays an important role in IAV infection of human lymphocytes, even as that structure also serves to support development of the adaptive immune response [24]. Lymphocyte infection was decreased in a dose-dependent manner when anti-intercellular adhesion molecule-1 (ICAM-1) antibody was added to PBMC cultures to prevent clustering between monocytes/macrophages and lymphocytes.…”

HLA-associated protection of lymphocytes during influenza virus infection

“…We previously showed that human monocyte/macrophage and lymphocyte interaction after exposure to influenza virus, including H1N1, H2N2 and H3N2 strains, is required for synthesis of viral proteins by lymphocytes [ 15 , 16 ]. In recent studies, we have used cells from individuals who were on a panel of slightly more than 100 subjects who had been serologically HLA-typed.…”

“…The current studies were undertaken in response to some surprising HLA-related results in studies of the requirement for monocyte/macrophage participation for influenza virus infection of human lymphocytes [ 15 , 16 ]. Those studies showed that influenza virus infection of human lymphocytes occurs in the immune cell cluster of the developing antiviral response.…”