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Blood, 12 March 2009, Vol. 113, No. 11, pp. 2434-2441.
Prepublished online as a Blood First Edition Paper on October 30, 2008; DOI 10.1182/blood-2008-05-156836.
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Submitted May 13, 2008
Accepted October 20, 2008
The strength of inhibitory input during education quantitatively tunes the functional responsiveness of individual natural killer cells
Petter Brodin, Tadepally Lakshmikanth, Sofia Johansson, Klas Karre, and Petter Hoglund*
Department of Microbiology, Tumor and Cell biology (MTC), Strategic Research Center IRIS, Karolinska Institutet, Stockholm, Sweden
* Corresponding author; email: petter.hoglund{at}ki.se.
Natural killer (NK) cells express inhibitory receptors for MHC class I. If self MHC is downregulated, or absent, lack of inhibition triggers "missing self" killing. NK cells developing in the absence of MHC class I are hypo-responsive, demonstrating that MHC class I molecules are required for NK cell education. Here, we show that the number and the type of MHC class I alleles that are present during NK cell education quantitatively determine the frequency of responding NK cells, the number of effector functions in individual NK cells as well as the amount of IFN- production in NK cells of specific Ly49 subsets. A relationship between the extent of inhibitory signals during education and functional responsiveness was corroborated by an enhanced probability of NK cells expressing more than one inhibitory receptor for a single host self MHC class I allele to degranulate after activation. Our data suggest that the capacity of an individual NK cell to respond to stimulation is quantitatively controlled by the extent of inhibitory signals that are received from MHC class I molecules during NK cell education.
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