Corresponding author's email: r.hendriks@erasmusmc.nlThe two different B cell compartments, B-1 cells and conventional B cells have differential roles during infection with influenza Rationale.virus in the lungs. Early during the infection, CD5 B-1 cells accumulate in the draining lymph nodes, do not proliferate in response to + antigen-specific stimulation, but differentiate locally in a T-cell independent manner into short-lived polyreactive IgM-secreting cells. On the other hand, conventional B cell responses include T-cell dependent antigen-specific clonal expansion, followed by differentiation into plasma cells that generally have switched their isotype. In a later phase of the infection, inducible bronchus associated lymphoid tissue is generated which importantly contributes to the production of virus-specific plasma cells. Mice deficient for Bruton's tyrosine kinase (Btk), which mainly functions to transmit signals downstream of the B cell receptor, lack CD5 B-1 B cells but their T cell-dependent B cell + responses are thought to be intact.Here, we analyzed the role of Btk in the humoral immune response to pulmonary infection with H3N2 influenza virus in the Methods. mouse. Btk-deficient mice and wild-type control mice were infected with X31 influenza virus and analyzed at various time points up to 25 days after intranasal infection.We found that in Btk-deficient mice weight loss upon virus infection was significantly higher and recovery was profoundly Results. hampered. At 5-7 days post infection, B-1 B lymphocytes were absent and IgM and IgG3 levels were strongly reduced in the bronchoalveolar lavage (BAL) fluid of Btk-deficient mice, when compared with wild-type mice. Btk-deficient B cells showed an aberrant B cell activation profile , characterized by the accumulation of a population of activated CD19 CD138 B cells, which was absent in in vivo + low wild-type mice. Moreover, the numbers of germinal center B cells in the lungs were significantly reduced. Nevertheless, formation of inducible bronchus-associated lymphoid tissue and induction of T cell-dependent IgA and IgG2b antibodies in the BAL were not affected by the absence of Btk. Importantly, we found that serum levels of virus-specific antibodies were significantly reduced. Taken together, these data show that Btk is crucially involved in multiple components of the host defense mechanism Conclusions. against influenza, not only for B-1 cell-mediated local IgM production, but also for the efficient T-cell dependent generation of virus-specific antibodies in the serum. This abstract is funded by: VIRGO grant Am J Respir Crit Care Med

Checkpoint blockage has revolutionized cancer treatment. NKG2A is an inhibitory receptor expressed by cytotoxic lymphocytes, including NK cells. In contrast to other checkpoint inhibitory antibodies, anti-NKG2A antibodies have shown only limited success. Nevertheless, recent studies highlight the importance of targeting the NKG2A pathway in cancer treatment. NK cells have seen increased attention as safe and competent effector cells for adoptive cell therapy, making it important to effectively target the NKG2A pathway. Therefore, we hypothesized that genetic deletion of KLRC1, the gene encoding NKG2A, in human NK cells is an effective and safe way to improve anti-tumor responses.

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