Nonhuman primate models of human immunology

Abstract

Nonhuman primates have been used for biomedical research for several decades. The high level of genetic homology to humans coupled with their outbred nature has made nonhuman primates invaluable preclinical models. In this review, we summarize recent advances in our understanding of the nonhuman primate immune system, with special emphasis on studies carried out in rhesus macaque (Macaca mulatta). We highlight the utility of nonhuman primates in the characterization of immune senescence and the evaluation of new interventions to slow down the aging of the immune system.

FIG. 1.

The immune system can be broadly divided into innate and adaptive branches. This figure highlights the key cellular components of each branch. Innate immunity is mostly mediated by dendritic cells (DC), natural killer (NK) cells, macrophages, and neutrophils. These cells use germline-encoded receptors to recognize pathogens. Adaptive immune response is mediated by T and B cells that express antigen receptors that recognize specific pathogens. The functions of these cells are discussed in more detail throughout the review.

FIG. 2.

Identification of dendritic cell subsets in rhesus macaques. Dendritic cells (DCs) can be identified as nonlymphocytes (CD3^negCD20^neg) that express MHC-II molecules (HLA-DR^pos) and lack the expression of CD14. DCs can be subdivided into myeloid DC and plasmacytoid DC based on the expression of CD11c and CD123. A minor subset does not express either of these markers.

FIG. 3.

Identification of circulating natural killer cells in rhesus macaques. Peripheral blood resident NK cells can be identified as CD3^negCD20^negDR^neg cells. The NK cells can then be subdivided into two subsets based on the expression of CD16: cytolytic NK cells (CD16^pos); and inflammatory-cytokine producing NK cells (CD16^neg).

FIG. 4.

Delineation of B cell subsets in rhesus macaques. As described for humans, circulating B cells can be subdivided into three subsets based on the expression of CD27 and IgD. Naive B cells are identified as IgD^posCD27^neg and memory B cells are IgD^negCD27^pos. In addition to these two main subsets, a third transitional subset referred as marginal zone-like B cells can be identified as IgD^pos CD27^pos. Both memory and marginal-zone like B cells contain somatic mutations in their B cell receptors, indicative of the fact that they have responded to antigens.

FIG. 5.

Delineation of rhesus macaque T cell subsets. T cells can be broadly subdivided into three subsets based on the expression of CD28 and CD95. Naive T cells are identified as CD28^posCD95^neg, central memory T cells are CD28^posCD95^neg, and effector memory T cell are CD28^negCD95^neg (A and B). The definition of memory T cells can be further refined based on the expression of CCR7 as described for human T cells. (C) and (D) show CD95^pos CD4 and CD8 memory T cells. The expression of CCR7 together with CD28 allows the identification of central memory, effector memory, and transitional central memory T cells that are differentiating to effector memory.

FIG. 6.

Nonlymphoid T cells do not express CCR7. T cells isolated from bronchial alveolar lavage are all memory phenotype based on CD95 expression. Furthermore, BAL-resident T cells lack the expression of CCR7.

FIG. 7.

Advanced age is accompanied by severe loss of naive T cells in rhesus macaques. Frequency of naive, central memory (CM), and effector memory (EM) T cells was determined based on the expression of CD28 and CD95 in juvenile (∼1 year of age, n = 12), adult (5–10 years of age, n = 35) and aged (>17 years of age, n = 25). Cross sectional analysis indicates that, as described for humans, increasing age is associated with the loss of circulating naive T cells. Thus, rhesus macaques are a robust model to study mechanisms underlying T cell senescence.