The causes and consequences of variation in human cytokine production in health

Cytokines are important cell-signaling molecules that activate and modulate immune responses. Major factors influencing cytokine variation in healthy individuals are host genetics, non-heritable factors and the microbiome. Genetic variation accounts for a significant part of heterogeneity in cytokine production by peripheral blood mononuclear cells. Variation in cytokines such as IL-6 and IL-6Ra is strongly influenced by heritability, suggesting an evolutionarily pressure for their genetic regulation that potentially contributes to differences in immune responsiveness between human populations. Non-heritable factors, including age, body weight and environmental variables such as seasonality, drive variation in baseline cytokine levels. Age further affects pathogen-induced lymphocyte-derived cytokine responses, whereas seasonality affects monocyte-derived cytokine production in response to influenza virus, Coxiella burnetti or Cryptococcus neoformans. Another influential factor that shapes the immune system is the human microbiome. Microbes and microbial products (e.g. short-chain fatty acids and tryptophan metabolites) possess strong immunomodulatory effects, induce regulatory T cells and lead to the diversification of B cells and the production of specific antibodies. In particular, differential TNFα and IFNγ production is associated with the gut microbiome. Understanding causes of variation in the healthy human immune system can reveal factors that lead to aberrant cytokine production in immune-related disorders.