Diet has a strong influence on the intestinal microbiota in both humans and animal models. It is well established that microbial colonization is required for normal development of the immune system and that specific microbial constituents prompt the differentiation or expansion of certain immune cell subsets. Nonetheless, it has been unclear how profoundly diet might shape the primate immune system or how durable the influence might be. We show that breast-fed and bottle-fed infant rhesus macaques develop markedly different immune systems, which remain different 6 months after weaning when the animals begin receiving identical diets. In particular, breast-fed infants develop robust populations of memory T cells as well as T helper 17 (T_H17) cells within the memory pool, whereas bottle-fed infants do not. These findings may partly explain the variation in human susceptibility to conditions with an immune basis, as well as the variable protection against certain infectious diseases.

Nonhuman primates are critically important animal models in which to study complex human diseases, understand biological functions, and address the safety of new diagnostics and therapies proposed for human use. They have genetic, physiologic, immunologic, and developmental similarities when compared to humans and therefore provide important preclinical models of human health and disease. This review highlights select research areas that demonstrate the importance of nonhuman primates in translational research. These include pregnancy and developmental disorders, infectious diseases, gene therapy, somatic cell genome editing, and applications of in vivo imaging. The power of the immune system and our increasing understanding of the role it plays in acute and chronic illnesses are being leveraged to produce new treatments for a range of medical conditions. Given the importance of the human immune system in health and disease, detailed study of the immune system of nonhuman primates is essential to advance preclinical translational research. The need for nonhuman primates continues to remain a high priority, which has been acutely evident during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) global pandemic. Nonhuman primates will continue to address key questions and provide predictive models to identify the safety and efficiency of new diagnostics and therapies for human use across the lifespan.

Although modern clinical practices such as cesarean sections and perinatal antibiotics have improved infant survival, treatment with broad-spectrum antibiotics alters intestinal microbiota and causes dysbiosis. Infants exposed to perinatal antibiotics have an increased likelihood of life-threatening infections, including pneumonia. Here, we investigated how the gut microbiota sculpt pulmonary immune responses, promoting recovery and resolution of infection in newborn rhesus macaques. Early-life antibiotic exposure interrupted the maturation of intestinal commensal bacteria and disrupted the developmental trajectory of the pulmonary immune system, as assessed by single-cell proteomic and transcriptomic analyses. Early-life antibiotic exposure rendered newborn macaques more susceptible to bacterial pneumonia, concurrent with increases in neutrophil senescence and hyperinflammation, broad inflammatory cytokine signaling, and macrophage dysfunction. This pathogenic reprogramming of pulmonary immunity was further reflected by a hyperinflammatory signature in all pulmonary immune cell subsets coupled with a global loss of tissue-protective, homeostatic pathways in the lungs of dysbiotic newborns. Fecal microbiota transfer was associated with partial correction of the broad immune maladaptations and protection against severe pneumonia. These data demonstrate the importance of intestinal microbiota in programming pulmonary immunity and support the idea that gut microbiota promote the balance between pathways driving tissue repair and inflammatory responses associated with clinical recovery from infection in infants. Our results highlight a potential role for microbial transfer for immune support in these at-risk infants.

Early infant diet has significant impacts on the gut microbiota and developing immune system. We previously showed that breast-fed and formula-fed rhesus macaques develop significantly different gut microbial communities, which in turn are associated with different immune systems in infancy. Breast-fed animals manifested greater T cell activation and proliferation and harbored robust pools of T helper 17 (T_H17) cells. These differences were sustained throughout the first year of life. Here we examine groups of juvenile macaques (approximately 3 to 5 y old), which were breast-fed or formula-fed in infancy. We demonstrate that juveniles breast-fed in infancy maintain immunologic differences into the fifth year of life, principally in CD8⁺ memory T cell activation. Additionally, long-term correlation networks show that breast-fed animals maintain persistent relationships between immune subsets that are not seen in formula-fed animals. These findings demonstrate that infant feeding practices have continued influence on immunity for up to 3 to 5 y after birth and also reveal mechanisms for microbial modulation of the immune system.

Interindividual immune variability is driven predominantly by environmental factors, including exposure to chronic infectious agents such as cytomegalovirus (CMV). We investigated the effects of rhesus CMV (RhCMV) on composition and function of the immune system in young macaques. Within months of infection, RhCMV was associated with impressive changes in antigen presenting cells, T cells, and NK cells—and marked expansion of innate-memory CD8⁺ T cells. These cells express high levels of NKG2A/C and the IL-2 and IL-15 receptor beta chain, CD122. IL-15 was sufficient to drive differentiation of the cells in vitro and in vivo. Expanded NKG2A/C⁺CD122⁺CD8⁺ T cells in RhCMV-infected macaques, but not their NKG2-negative counterparts, were endowed with cytotoxicity against class I–deficient K562 targets and prompt IFN-γ production in response to stimulation with IL-12 and IL-18. Because RhCMV clone 68-1 forms the viral backbone of RhCMV-vectored SIV vaccines, we also investigated immune changes following administration of RhCMV 68-1–vectored SIV vaccines. These vaccines led to impressive expansion of NKG2A/C⁺CD8⁺ T cells with capacity to inhibit SIV replication ex vivo. Thus, CMV infection and CMV-vectored vaccination drive expansion of functional innate-like CD8 cells via host IL-15 production, suggesting that innate-memory expansion could be achieved by other vaccine platforms expressing IL-15.

Background: Both the gut microbiota and chronic viral infections have profound effects on host immunity, but interactions between these influences have been only superficially explored. Cytomegalovirus (CMV), for example, infects approximately 80% of people globally and drives significant changes in immune cells. Similarly, certain gut-resident bacteria affect T-cell development in mice and nonhuman primates. It is unknown if changes imposed by CMV on the intestinal microbiome contribute to immunologic effects of the infection. Results: We show that rhesus cytomegalovirus (RhCMV) infection is associated with specific differences in gut microbiota composition, including decreased abundance of Firmicutes, and that the extent of microbial change was associated with immunologic changes including the proliferation, differentiation, and cytokine production of CD8⁺ T cells. Furthermore, RhCMV infection disrupted the relationship between short-chain fatty acid producers and Treg/Th17 balance observed in seronegative animals, showing that some immunologic effects of CMV are due to disruption of previously existing host-microbe relationships. Conclusions: Gut microbes have an important influence on health and disease. Diet is known to shape the microbiota, but the influence of concomitant chronic viral infections is unclear. We found that CMV influences gut microbiota composition to an extent that is correlated with immunologic changes in the host. Additionally, pre-existing correlations between immunophenotypes and gut microbes can be subverted by CMV infection. Immunologic effects of CMV infection on the host may therefore be mediated by two different mechanisms involving gut microbiota.