PT  - JOURNAL ARTICLE
AU  - Mathieu Le Gars
AU  - Christof Seiler
AU  - Alexander W. Kay
AU  - Nicholas L. Bayless
AU  - Elsa Sola
AU  - Elina Starosvetsky
AU  - Lindsay Moore
AU  - Shai S. Shen-Orr
AU  - Natali Aziz
AU  - Purvesh Khatri
AU  - Cornelia L. Dekker
AU  - Gary E. Swan
AU  - Mark M. Davis
AU  - Susan Holmes
AU  - Catherine A. Blish
TI  - CD38 contributes to human natural killer cell responses through a role in immune synapse formation
AID  - 10.1101/349084
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 349084
4099  - http://biorxiv.org/content/early/2019/05/24/349084.short
4100  - http://biorxiv.org/content/early/2019/05/24/349084.full
AB  - Natural killer (NK) cells use a diverse array of activating and inhibitory surface receptors to detect threats and provide an early line of defense against viral infections and cancer. Here, we demonstrate that the cell surface protein CD38 is a key human NK cell functional receptor through a role in immune synapse formation. CD38 expression marks a mature subset of human NK cells with a high functional capacity. NK cells expressing high levels of CD38 display enhanced killing and IFN-γ secretion in response to influenza virus-infected and tumor cells. Inhibition of CD38 enzymatic activity does not influence NK cell function, but blockade of CD38 and its ligand CD31 abrogates killing and IFN-γ expression in response to influenza-infected cells. Blockade of CD38 on NK cells similarly inhibits killing of tumor cells. CD38 localizes and accumulates at the immune synapse between NK cells and their targets, and blocking CD38 severely abrogates the ability of NK cells to form conjugates and immune synapses with target cells. Thus, CD38 plays a critical role in NK cell immune synapse formation. These findings open new avenues in immunotherapeutic development for cancer and infection by revealing a critical role for CD38 in NK cell function.