Identification of distinct human invariant natural killer T-cell response phenotypes to alpha-galactosylceramide

Dec 6, 2008BMC immunology

Different types of human natural killer T-cell responses to alpha-galactosylceramide

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Abstract

In a study of 25 healthy human donors, the in-vitro expansion of iNKT cells in response to CD1d ligand activation varied significantly among individuals.

All donors had similar numbers of circulating iNKT cells, but their growth rates in response to CD1d ligands and IL-2 were highly variable.
Two distinct patterns of iNKT expansion were identified: 'strong' responders and 'poor' responders.
Donor response phenotypes did not show correlation with age, gender, or the frequency of circulating iNKT cells.
Adding recombinant human interleukin 4 (IL-4) increased iNKT cell expansion in 'poor' responders but not to the levels seen in 'strong' responders.
In 'strong' responder donors, the addition of IL-4 did not significantly change the frequency of iNKT cells in the expanded population.

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BACKGROUND: Human CD1d-restricted, invariant natural killer T cells (iNKT) are a unique class of T lymphocytes that recognise glycolipid antigens such as alpha-galactosylceramide (alphaGalCer) and upon T cell receptor (TCR) activation produce both Th1 and Th2 cytokines. iNKT cells expand when cultured in-vitro with alphaGalCer and interleukin 2 (IL-2) in a CD1d-restricted manner. However, the expansion ratio of human iNKT cells varies between individuals and this has implications for attempts to manipulate this pathway therapeutically. We have studied a panel of twenty five healthy human donors to assess the variability in their in-vitro iNKT cell expansion responses to stimulation with CD1d ligands and investigated some of the factors that may influence this phenomenon.

RESULTS: Although all donors had comparable numbers of circulating iNKT cells their growth rates in-vitro over 14 days in response to a range of CD1d ligands and IL-2 were highly donor-dependent. Two reproducible donor response patterns of iNKT expansion were seen which we have called 'strong' or 'poor' iNKT responders. Donor response phenotype did not correlate with age, gender, frequency of circulating iNKT, or with the CD1d ligand utilised. Addition of exogenous recombinant human interleukin 4 (IL-4) to 'poor' responder donor cultures significantly increased their iNKT proliferative capacity, but not to levels equivalent to that of 'strong' responder donors. However in 'strong' responder donors, addition of IL-4 to their cultures did not significantly alter the frequency of iNKT cells in the expanded CD3+ population.

CONCLUSION: (i) in-vitro expansion of human iNKT cells in response to CD1d ligand activation is highly donor variable, (ii) two reproducible patterns of donor iNKT expansion were observed, which could be classified into 'strong' and 'poor' responder phenotypes, (iii) donor iNKT response phenotypes did not correlate with age, gender, frequency of circulating iNKT cells, or with the CD1d ligand utilised, (iv) addition of IL-4 to 'poor' but not 'strong' responder donor cultures significantly increased their in-vitro iNKT cell expansion to alphaGalCer.

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