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The dynamics of γδ T cell frequencies and functions through the course of SARS-CoV-2 infection in rhesus macaques and African green monkeys reveals that Vδ1 γδ T cells are involved in the early immune response to SARS-CoV-2 infection.

BackgroundAlthough BCG vaccine protects infants from tuberculosis (TB), it has limited efficacy in adults against pulmonary TB. Further, HIV coinfection significantly increases the risk of developing active TB. In the lack of defined correlates of protection in TB disease, it is essential to explore immune responses beyond conventional CD4 T cells to gain a better understanding of the mechanisms of TB immunity.MethodsHere, we evaluated unconventional lipid-reactive T cell responses in cynomolgus macaques following aerosol BCG inoculation and examined the impact of subsequent SIV infection on these responses. Immune responses to cellular lipids of M. bovis and M. tuberculosis were examined ex vivo in peripheral blood and bronchioalveolar lavage (BAL).ResultsPrior to BCG inoculation, innate-like IFN-γ responses to mycobacterial lipids were observed in T cells. Aerosol BCG exposure induced an early increase in frequencies of BAL γδT cells, a dominant subset of lipid-reactive T cells, along with enhanced IL-7R and CXCR3 expression. Further, BCG exposure stimulated greater IFN-γ responses to mycobacterial lipids in peripheral blood and BAL, suggesting the induction of systemic and local Th1-type response in lipid-reactive T cells. Subsequent SIV infection resulted in a significant loss of IL-7R expression on blood and BAL γδT cells. Additionally, IFN-γ responses of mycobacterial lipid-reactive T cells in BAL fluid were significantly lower in SIV-infected macaques, while perforin production was maintained through chronic SIV infection.ConclusionsOverall, these data suggest that despite SIV-induced decline in IL-7R expression and IFN-γ production by mycobacterial lipid-reactive T cells, their cytolytic potential is maintained. A deeper understanding of anti-mycobacterial lipid-reactive T cell functions may inform novel approaches to enhance TB control in individuals with or without HIV infection.

Background: Clinical measurements commonly used to evaluate overall health of laboratory animals including complete blood count, serum chemistry, weight, and immunophenotyping, differ with respect to age, development, and environment. This report provides comprehensive clinical and immunological reference ranges for pediatric rhesus macaques over the first year of life.Methods: We collected and analyzed blood samples from 151 healthy rhesus macaques, aged 0–55 weeks, and compared mother-reared infants to two categories of nursery-reared infants; those on an active research protocol and those under derivation for the expanded specific-pathogen-free breeding colony. Hematology was performed on EDTA-anticoagulated blood using a Sysmex XT2000i, and serum clinical chemistry was performed using the Beckman AU480 chemistry analyzer. Immunophenotyping of whole blood was performed with immunofluorescence staining and subsequent flow cytometric analysis on a BD LSRFortessa. Plasma cytokine analysis was performed using a Millipore multiplex Luminex assay.Results: For hematological and chemistry measurements, pediatric reference ranges deviate largely from adults. Comparison of mother-reared and nursery-reared animals revealed that large differences depend on rearing conditions and diet. Significant differences found between two nursery-reared cohorts (research and colony animals) indicate large influences of experimental factors and anesthetic events on these parameters. Immune cells and cytokine responses presented with distinct patterns for infants depending on age, birth location, and rearing conditions.Conclusions: Our results illustrate how the immune system changed over time and that there was variability among pediatric age groups. Reference ranges of results reported here will support interpretations for how infection and treatment may skew common immune correlates used for assessment of pathology or protection in research studies as well as help veterinarians in the clinical care of infant non-human primates. We highlighted the importance of using age-specific reference comparisons for pediatric studies and reiterated the utility of rhesus macaques as a model for human studies. Given the rapid transformation that occurs in multiple tissue compartments after birth and cumulative exposures to antigens as individuals grow, a better understanding of immunological development and how this relates to timing of infection or vaccination will support optimal experimental designs for developing vaccines and treatment interventions.

Monocytes/macrophages are a diverse group of cells that act as first responders in innate immunity and then as mediators for adaptive immunity to help clear infections. In performing these functions, however, the macrophage inflammatory responses can also contribute to pathogenesis. Various monocyte and tissue macrophage subsets have been associated with inflammatory disorders and tissue pathogeneses such as occur during HIV infection. Non-human primate research of simian immunodeficiency virus (SIV) has been invaluable in better understanding the pathogenesis of HIV infection. The question of HIV/SIV-infected macrophages serving as a viral reservoir has become significant for achieving a cure. In the rhesus macaque model, SIV-infected macrophages have been shown to promote pathogenesis in several tissues resulting in cardiovascular, metabolic, and neurological diseases. Results from human studies illustrated that alveolar macrophages could be an important HIV reservoir and humanized myeloid-only mice supported productive HIV infection and viral persistence in macrophages during ART treatment. Depletion of CD4+ T cells is considered the primary cause for terminal progression, but it was reported that increasing monocyte turnover was a significantly better predictor in SIV-infected adult macaques. Notably, pediatric cases of HIV/SIV exhibit faster and more severe disease progression than adults, yet neonates have fewer target T cells and generally lack the hallmark CD4+ T cell depletion typical of adult infections. Current data show that the baseline blood monocyte turnover rate was significantly higher in neonatal macaques compared to adults and this remained high with disease progression. In this review, we discuss recent data exploring the contribution of monocytes and macrophages to HIV/SIV infection and progression. Furthermore, we highlight the need to further investigate their role in pediatric cases of infection.