Co-evolution of KIR2DL3 with HLA-C in a human population retaining minimal essential diversity of KIR and HLA class I ligands

Abstract

Natural killer (NK) cells contribute to immunity and reproduction.Guiding these functions, and NK cell education, are killer cell Ig-like receptors (KIR), NK cell receptors that recognize HLA class I. In most human populations, these highly polymorphic receptors and ligands combine with extraordinary diversity. To assess how much of this diversity is necessary, we studied KIR and HLA class I at high resolution in the Yucpa, a small South Amerindian population that survived an approximate 15,000-year history of population bottleneck and epidemic infection, including recent viral hepatitis. The Yucpa retain the three major HLA epitopes recognized by KIR. Through balancing selection on a few divergent haplotypes the Yucpa maintain much of the KIR variation found worldwide. HLA-C*07, the strongest educator of C1-specific NK cells, has reached unusually high frequency in the Yucpa. Concomitantly, weaker variants of the C1 receptor, KIR2DL3, were selected and have largely replaced the form of KIR2DL3 brought by the original migrants from Asia. HLA-C1 and KIR2DL3 homozygosity has previously been correlated with resistance to viral hepatitis. Selection of weaker forms of KIR2DL3 in the Yucpa can be seen as compensation for the high frequency of the potent HLA-C*07 ligand. This study provides an estimate of the minimal KIR-HLA system essential for long-term survival of a human population. That it contains all functional elements of KIR diversity worldwide, attests to the competitive advantage it provides, not only for surviving epidemic infections, but also for rebuilding populations once infection has passed.Amerindian ͉ immune diversity ͉ natural selection ͉ NK cells ͉ reproduction

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

“…There are only two common KIR haplotypes in the Yucpa (one A and one B ; see Fig. 2 for nomenclature), but between them they carry all of the expressed KIR genes 55. This situation is extremely unlikely without the impact of a form of natural selection called balancing selection, which maintains genetic variation of specific loci in the population 55.…”

“…2 for nomenclature), but between them they carry all of the expressed KIR genes 55. This situation is extremely unlikely without the impact of a form of natural selection called balancing selection, which maintains genetic variation of specific loci in the population 55. Indeed, all human populations studied to date have a representation of KIR A and B haplotypes51, 56 and the prevailing hypothesis is that the A haplotypes are good for fighting infection57, 58 whereas B haplotypes are more beneficial for reproduction 17, 59…”

“…Again, high‐resolution analysis of the Yucpa population yields further insight into this phenomenon. The population has extremely high frequency of HLA‐C7 and corresponding high frequency of a KIR2DL3 allotype, unique to the Yucpa, having reduced C7 binding 55. By comparison, the KhoeSan population from Southern Africa has one of the highest aggregate frequencies of HLA‐C allotypes expressing the C2 motif.…”

“…KIR2DL2/3 allotypes form a continuum of binding strength and specificity that includes several inactivated or weakened variants 34, 40, 55, 107, 108, 109. Studies using soluble KIR showed that allotype KIR2DL3*001 is C1‐specific and binds relatively weakly, whereas KIR2DL2*001 binds more strongly and has cross‐reactivity with C2 103.…”

“…Studies using soluble KIR showed that allotype KIR2DL3*001 is C1‐specific and binds relatively weakly, whereas KIR2DL2*001 binds more strongly and has cross‐reactivity with C2 103. In addition to those directly at the binding site, the substitutions that cause these functional differences may affect the angle or orientation of the binding domain,55, 103 or the efficiency of receptor clustering at the cell surface 99, 108. Allelic polymorphism also influences the functional properties of KIR2DL1, which has evolved to be a highly specific receptor for HLA‐C2 110.…”