(552) Impact of Myeloid-Derived Suppressor Cells on T Cell Function in Children With S aureus Infection

Introduction: Staphylococcus aureus (SA) is a leading bacterial cause of childhood hospitalization, including severe infections such as sepsis and pneumonia. Children with SA infection have impaired T cell function, but the mechanisms are unknown. Myeloid-Derived Suppressor Cells (MDSC) are immature myeloid cells that potently suppress T cell function by several mechanisms, including production of arginase1 (arg1) to deplete the environment of arginine necessary for T cell function. While MDSC suppress T cells in SA mouse models, their role in human SA infection is unclear. We hypothesize that MDSC are expanded in children with SA infection and contribute to T cell impairment.

Methods: This is a prospective observational study of children admitted to the hospital with PCR or culture confirmed SA infection. Age-matched healthy children (HC) were enrolled as controls. Peripheral blood mononuclear cells were isolated and stained to quantify MDSC (CD45+/HLA-DR-/CD33+/CD11b+), granulocytic (G)-MDSC (CD15+) and monocytic (M)-MDSC (CD14+) subsets, and T cell subsets (CD4+/CD8+). IFNγ-secreting T cells were quantified by ELISpot following stimulation by PMA/ionomycin.

Results: 33 SA-infected subjects (SAS) (70% male, median age 9.5 [1.2-18] yrs) and 20 HC (60% male, 10.4 [1.3-17.8] yrs, p=0.54) were enrolled. Compared to HC, SAS had more MDSC (1992 [66.38-10007] vs. 526 [15.74-1178] p=0.008) and M-MDSC (1241 [43-6802] vs. 494 [14-1160], p< 0.001). Arg1 was highly expressed on MDSC in SAS (97% [38-100]). CD4+/CD8+ T cells frequencies were similar between SAS and HC (CD4+ 932 [156-4644.2] vs 1477 [696.2-4364.5] p=0.22). IFNγ-secreting T cells were decreased in SAS compared to HC (499 [251-696] vs.1000 [554-1000] p< 0.0001). Importantly, a higher percentage of MDSC was associated with decreased IFNγ-secreting T cells in SAS (R2=0.4, p=0.002).

Conclusions: Our results show that MDSC, particularly M-MDSC, are expanded in SAS compared to HC and express arg1. Moreover, despite similar T cell numbers, SAS had impaired T cell function that was associated with MDSC expansion. These findings suggest that MDSC expansion impairs T cell function via expression of arg1. Further studies are needed to confirm the arg1 pathway as a potential therapeutic target to rescue MDSC-mediated T cell suppression in children with SA infection.