The Variable Genomic NK Cell Receptor Locus Is a Key Determinant of CD4+ T Cell Responses During Viral Infection.

Adora Lin,Kasper Hoebe,Kristin Lampe,David A Hildeman,Sarah A Hummel,Michael Jordan,Jana Raynor

doi:10.3389/fimmu.2020.00197

Adora Lin, Kasper Hoebe + Show 5 more

Open Access

https://doi.org/10.3389/fimmu.2020.00197

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Abstract

Increasing evidence points to a key role for NK cells in controlling adaptive immune responses. In studies examining the role of CD1d on CD4+ T cell responses, we found that a line of CD1d-deficient mice on the C57BL/6J background had a homozygous 129 locus on chromosome 6 containing the entire NK cell gene cluster. Mice possessing this locus (C57BL/6.NKC129) displayed a >10-fold reduction in antigen-specific CD4+ T cell responses after intracranial infection with lymphocytic choriomeningitis virus (LCMV). Neither parental strain displayed defects in viral-specific CD4+ T cell responses. Interestingly, following infection, increased numbers of NK cells accumulated in the lymph nodes of C57BL/6.NKC129 mice and displayed enhanced in vivo functionality. Moreover, depletion of NK cells with anti-asialo-GM-1 antibody in C57BL/6.NKC129 mice resulted in a >20-fold increase in viral-specific CD4+ T cell responses. Mechanistically, we found that dendritic cell antigen presentation and early type I IFN production were significantly decreased in C57BL/6.NKC129 mice, but were restored in perforin-deficient C57BL/6.NKC129 mice or following NK depletion. Together, these data reveal that the variable genomic regions containing the activating/inhibitory NK cell receptors are key determinants of antigen-specific CD4+ T cell responses, controlling type I IFN production and the antigen-presenting capacity of dendritic cells.

Highlights

Cytotoxic immune cells are critical for the clearance of altered-self, such as tumor cells and pathogen-infected cells
The natural killer (NK) gene complex (NKC) is evolutionarily diverse and has high allelic polymorphism among different mouse strains [24]. This genetic variation has been utilized to better understand the regulation of NK cell homeostasis and function by generating chimera mice at the NKC locus [25]. Such studies have demonstrated that NK functionality is altered when the 129 genome at the NKC locus is inserted in the C57BL/6 background [25, 36]
Using an independent BL/6.NKC129 congenic mouse line, we showed that NK cells from BL/6.NKC129 mice have increased function relative to C57BL/6 mice during lymphocytic choriomeningitis virus (LCMV) infection and have linked this increased function to negative regulation of anti-viral CD4+ T cell responses

Summary

Introduction

Cytotoxic immune cells are critical for the clearance of altered-self, such as tumor cells and pathogen-infected cells. Cells involved in both innate and adaptive immunity have cytotoxic function, including natural killer T (NKT), natural killer (NK), and CD8+ T cells. NKT cells are defined as an innate T cell lineage that express CD3 and αβ T cell receptor (TCR), as well as NK cell markers, such as NK1.1 [6]. NKT cells display a limited TCR repertoire, with most expressing a rearrangement of the Vα14 and Jα18 segments paired with Vβ2, 7, or 8.2

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