Genetic control of murine invariant natural killer T-cell development dynamically differs dependent on the examined tissue type

Abstract

Previous studies using gene-targeted mutant mice revealed several molecules important for the development or function of invariant natural killer (iNKT)-cells. However, these gene knockout mice represent cases that are rare in humans. Thus, it remains unclear how naturally occurring allelic variants of these genes or others regulate the numerical and functional diversity of iNKT-cells in both mice and humans. Studies in humans are mostly limited to iNKT-cells in peripheral blood (PB). It is not known if the relative distribution of iNKT-cells between PB and other lymphoid organs is correlated or under common genetic control. To initially address these questions, we analyzed iNKT-cells in the spleen, thymus, and PB of 38 inbred mouse strains. Percentages of iNKT-cells in these three anatomical sites varied significantly in a strain-dependent manner. The correlation between PB and spleen was moderate, and none was observed between PB and thymus. Similarly, proportions of the CD4-expressing subset of iNKT-cells differed significantly among inbred strains. The percentages of CD4-positive iNKT-cells displayed a strong correlation between PB and spleen although it remained poor between PB and thymus. Genome-wide association studies across strains identified only partially overlapping loci associated with variability of iNKT-cell frequencies within and between differing anatomical sites.

Adjuvant effects of therapeutic glycolipids administered to a cohort of NKT cell-diverse pigs

“…Although the range of NKT cell frequencies was large for all tissues tested, they were also similar to what has previously been reported for pigs and other species (Chen et al, 2012;Montoya et al, 2007;Renukaradhya et al, 2011;Thierry et al, 2012). Furthermore, our finding that NKT cell concentrations in spleen are higher and more variable compared to PB and lymph nodes is consistent with the distribution of NKT cells in mice (Chen et al, 2012;Watarai et al, 2012). Also similar to mice, we found a moderate correlation in the frequency of NKT cells between PB and spleen within individual pigs (Chen et al, 2012).…”

“…Furthermore, our finding that NKT cell concentrations in spleen are higher and more variable compared to PB and lymph nodes is consistent with the distribution of NKT cells in mice (Chen et al, 2012;Watarai et al, 2012). Also similar to mice, we found a moderate correlation in the frequency of NKT cells between PB and spleen within individual pigs (Chen et al, 2012). However, both blood and spleen were respectively weakly and not significantly correlated to CLN and MLN for NKT cells.…”

“…We employed the same strategy to survey NKT cell populations in a variety of tissues for a large cohort of genetically heterogeneous pigs slaughtered for meat through the University of Florida's meat sciences laboratory. Although the range of NKT cell frequencies was large for all tissues tested, they were also similar to what has previously been reported for pigs and other species (Chen et al, 2012;Montoya et al, 2007;Renukaradhya et al, 2011;Thierry et al, 2012). Furthermore, our finding that NKT cell concentrations in spleen are higher and more variable compared to PB and lymph nodes is consistent with the distribution of NKT cells in mice (Chen et al, 2012;Watarai et al, 2012).…”

“…Although, high and low NKT cell-producing sows farrowed at the same time and in adjacent crates, piglets were born in a conventional farrowing house where environmental factors may have influenced NKT cell development during the first 2 weeks of life. However, it is likely much of the variation was due to genetic effects, because it is known that NKT cell development and homeostasis is strongly influenced by multiple loci in mice (Chen et al, 2007(Chen et al, , 2012Esteban et al, 2003). Differences in NKT cell frequency between litters may impact the health of piglets given that these immunoregulatory cells make important contributions to both innate and adaptive immunity against multiple pathogens, and appear to develop soon after birth when animals are most susceptible to infections.…”

Genetic control of murine invariant natural killer T cells maps to multiple type 1 diabetes regions

“…Recently, we extended the previous studies using a large panel of classical and wild-derived inbred mouse strains. Consistent with the observation in humans, we also demonstrated a substantial strain-dependent variation in the frequencies of thymic and splenic iNKT cells, and those circulating in the blood 11 . Taken together, these results indicate that the development of iNKT-cells is a complex trait controlled by multiple genetic variants in both humans and mice.…”