IIMMUNOLOGIN H1N1 : the respective roles of CD4, CD8, and NK cells in IFN- production in a healthy adult human population

Influenza is one of the most common respiratory diseases in humans and is potentially lethal in immunocompromised persons. It affects all types of people, from infants to the elderly, and is usually caused by types A and B of the influenza virus. Although efficient vaccines exist, investigations still need to be conducted to further improve such vaccines, in particular because of the high degree of virus variability, requiring annual vaccination . Antigenic variability is mostly due to changes in hemagglutinin (HA) and neuraminidase (NA) antigens. Among type A strains, 15 HA and 9 NA subtypes have been identified, and in humans 5 subtype combinations have been linked to flu pandemics since 1900 (the recent avian H5N1 outbreak has remained localized in Hong Kong and to a limited number of persons). In the past 20 years, the predominant A strain has been of the H3N2 subtype, while H1N1 has been isolated less frequently .

Antibodies to HA and NA play a critical role in protection , but because of the variability of these antigens the role of cellular responses directed in particular against more conserved internal proteins has been investigated. It has been demonstrated that this response was important during the first contact, as well as during subsequent influenza infections . Cellular responses may be cross-protective, involving cytotoxic T lymphocytes (CTLs) that are able to recognize epitopes shared by several subtypes . This type of response could then be useful in vaccination for generating a pool of persistent cross-reactive T lymphocytes . Gamma interferon (IFN-)-producing CD4 T cells can also favor viral elimination from nasal tissues  and, more generally, IFN- plays a critical role in cell-mediated immunity, stimulating macrophages and NK cell activity. Apart from CD4 T cells, IFN- is produced by CD8 T cells and NK cells, and these cells have been demonstrated to induce and upregulate early inflammatory and cytotoxic events . However, their role has not been extensively studied during secondary stimulation, a situation found in the great majority of the adult and elderly populations, after these individuals receive the flu vaccine, due to prior natural infection(s).

The respective roles of CD4, CD8, and NK cells in IFN- production in a healthy adult human population, we depleted these cellular subtypes before in vitro stimulation with flu antigens (inactivated split virus). We observed that some depletions induced an unexpected increase in spot numbers compared to the initial undepleted population, showing that cellular cross-regulations occur even during short in vitro stimulation with antigen.

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