# Age-Related Patterns of Type II Interferon Immunity: Implications for Intramacrophagic Infections and MSMD Diagnosis During Childhood

## TL;DR

This study explores how type II interferon immunity develops in children and its implications for diagnosing MSMD, a condition affecting the immune response to certain infections.

## Contribution

The study provides age-related insights into the maturation of type II interferon immunity and its role in MSMD diagnosis.

## Key findings

- Key components of the IL-12/IFN-γ axis remain stable across childhood, indicating consistent innate immune function.
- IFN-γ responses and anti-inflammatory cytokines increase with age, showing enhanced downstream signaling.
- T cell maturation, especially Th1, Th17, and Th1/17 subsets, progresses significantly between 6 and 8.6 years.

## Abstract

Type II interferon (IFN) immunity is crucial for controlling intramacrophagic infections, driven by the interaction between innate immunity (macrophage-derived IL-12) and adaptive immunity (Th-derived IFN-γ). This study examines the maturation of type II IFN immunity in 55 healthy children (ages 1–18) to enable proper identification of deficiencies as part of the diagnostic evaluation of Mendelian Susceptibility to Mycobacterial Diseases (MSMD). The IL-12/IFN-γ axis was assessed through: (1) cytokine production after mycobacterial stimulation (Luminex and ELISA for IFN-γ, IL-12p70, TNF, CXCL10, IL-1RA, IL-10, IL-1β and IL-6), (2) IFN-γR1/R2 expression on monocytes, and (3) STAT1 phosphorylation/dephosphorylation. T cell maturation (primary IFN-γ source) was evaluated via immunophenotyping (naïve/memory/activated, Th1; Th2; Th17; Th1/17; Tfh) and proliferation assays. Main findings: (1) stable expression/production of key components of the IL-12/IFN-γ axis (IFN-γ, IL-12, TNF, IFN-γR1/2, and STAT1 activity) across ages confirming the stability of innate immune function throughout childhood; (2) increasing responses to IFN-γ with age reflected by increased CXCL10 production, and increase in the IFN-γ counter-acting anti-inflammatory cytokines (IL-10, IL-1RA); and (3) progressive T cell maturation, including Th1, Th17 and Th1/17 subsets, with significant milestones between 6 and 8.6 years, while T cell proliferative capacity remained stable. These observations highlight the stability of IL-12/IFN-γ axis innate components with age, accompanied by enhanced downstream IFN-γ signaling, aligning with the maturation of Th cell compartment. These underscore the limited benefit of age-specific controls in the evaluation of IL-12/IFN-γ axis in MSMD diagnosis, while emphasizing the importance of T cell maturation in the overall type II IFN immunity.

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The online version contains supplementary material available at 10.1007/s10875-025-01955-2.