Influenza vaccination in immunosuppressed and healthy individuals : DC-induced regulatory NK cell-function

Infection with the human immunodeficiency virus (HIV) leads to immunosuppression, mainly
through depletion of CD4+ T cells. Anti-retroviral therapy (ART) inhibits virus replication and
thereby promotes recovery of T cell numbers and reconstitution of cellular immunity. Importantly,
ART improves control of opportunistic infections, increases quality of life and restores life
expectancy of HIV-infected individuals.
We assessed how HIV-infected individuals compare to HIV-negative individuals in terms of
mounting an influenza-vaccine specific humoral and cellular immune response. We were able to
show that the influenza-specific IgM- but not the IgG response was absent in HIV-infected
individuals with low CD4+ T cell counts. Moreover, expansion of IFN-γ secreting CD4+ T cells
was impaired. These findings point out the importance of building B cell memory while
immunological competence is maintained.
Fingolimod-treated individuals have –similar to HIV-infected untreated individuals– low CD4+ T
cell counts in their peripheral circulation. In the second section of the thesis we characterized
cellular and humoral immune responses to influenza-vaccine in fingolimod-treated patients
(diagnosed with multiple sclerosis), and in untreated healthy controls. Intriguingly, vaccinetriggered
T cells accumulated normally in blood of fingolimod-treated individuals, despite reduced
peripheral T cell counts. Concentrations of anti-influenza A/B IgM and IgG also increased
similarly in both groups. These results indicate that fingolimod-treated individuals can mount
vaccine-specific adaptive immune responses comparable to healthy controls.
Natural killer cells (NK cells) have the ability to link the innate to the adaptive immune system.
We determined the Killer-cell immunoglobulin-like receptor (KIR) genotype in two cohorts of
healthy and one cohort of HIV-infected individuals, and related genotype and influenza-vaccine
induced adaptive immune response(s). These experiments uncovered enhanced vaccinespecific
CD4+ T cell-immunity to be induced in HIV-negative but not HIV-positive individuals
bearing the KIR 2DS1/3DS1 genes. Following up on our observation that NK cell-receptor gene polymorphisms impact adaptive
immune responses we lastly tested the hypothesis that NK cells may directly impact the
interaction between dendritic cells (DCs) and T cells. Assessing this interaction in vitro we were
able to demonstrate that LPS-matured DCs, but not immature DCs, have the capacity to induce
immunosuppressive reactivity in autologous NK cells.