Natural Killer (NK) cells represent a pivotal player of innate immune responses, and may also positively or negatively affect the development, amplitude and persistence of adaptive responses. NK cells contribute to immune homeostasis and to the pathogenesis of autoimmune diseases, by producing cytokines and chemokines, and through direct cell-cell interactions. The impact of environmental factors in shaping the representativity of different NK cell subsets is increasingly appreciated. Human Cytomegalovirus (HCMV) infection profoundly affects NK cell compartment, and induces the expansion of a long-lived ¿memory¿ NK cell subset, endowed with enhanced CD16 (low affinity receptor for IgG)-dependent functional capabilities, in a fraction of seropositive subjects. The requirements for memory NK cell pool size, long-term persistence, and activation have not been fully characterized yet. It can be envisaged that chronic interaction with antibody (Ab)-opsonized cells may represent an efficient stimulus for selective memory NK cell expansion and/or maintenance in vivo, given their recognized hyperresponsivity to CD16-initiated signaling pathways, and based on ours' and others' in vitro evidence. Thanks to their exquisite sensitivity to Ab-opsonized cells, memory NK cells are placed in a privileged position for exerting a regulatory role in Ab-dependent autoimmune diseases. As an attempt to test the hypothesis that CD16/autoAb-driven signals play a role in shaping the in vivo memory NK cell pool in autoimmune diseases, we will conduct a pilot study in a cohort of HCMV+ patients affected by immune thrombocytopenia (ITP), an autoimmune disease where anti-platelet autoAbs play a major role. We will:
1. Analyze whether ITP condition associates with a quantitative alteration of the memory NK cell pool in vivo.
2. Evaluate the capability of autoAb-opsonized platelets to promote the selective expansion of memory NK cells in vitro.
No information exists in the literature on the possible dysregulation of memory NK cells in autoimmune condition; moreover, whether their CD16-dependent immunoregulatory functions may contribute to amplify/sustain, or rather be relevant for limiting/dampening autoaggressive immune responses is unknown. The results of our analysis on ITP patients will:
a) represent a proof-of-concept that could be verified in other antibody-based autoimmune conditions, to support a general mechanism for explaining in vivo dynamics of memory NK cells in the context of autoimmune diseases;
b) be a prerequisite for evaluating more in depth the functional outcomes of the interaction between memory NK cells and autoantibody-coated self cells, to assess their contribution to tissue damage;
c) be a prerequisite for analyzing the impact of their crosstalk with autoreactive T and B cells;
d) provide a rational basis for further studies aimed at the therapeutical manipulation of memory NK cells in autoimmune diseases.