It is not expected that autophagosome-like structures can mature into autolysosomes after degradation of the IAM in ATG conjugation–deficient
cells, which suggests that autophagic activity
remains at a very low level. It may explain the
phenotypic difference among ATG KO mice:
Embryonic lethality is observed in mice lacking
upstream ATGs—such as FIP200, ATG9A, and
ATG13 (20–22), whereas mice lacking ATG conjugation components, such as ATG3, ATG5, ATG7,
ATG12, and ATG16L1, can survive the embryonic
period (but die shortly after birth) (13, 18, 23–25).
So far, the function of ATG proteins has been
investigated only in the context of autophagosome formation, but our findings also revealed
a function of ATGs with regard to the maturation steps.
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We thank N. Tamura, S. Kawahara, and M. Yoshimura for help
with establishment of ATG knockout and rescued cells;
S. Yamaoka for the pMRXIP vector; Y. Tanaka for LAMP1 cDNA
and anti-LAMP1 antibody; A. Miyawaki for Venus, superenhanced
CFP, and mRFP cDNAs; M. Komatsu for ATG3 KO and ATG7 KO
cells; J.-L. Guan for FIP200 KO MEFs; T. Saitoh and S. Akira for
ATG9A KO and ATG14 KO MEFs; and T. Yasui for the pCG-VSV-G
and pCG-gag-pol plasmids. This work was supported by Japan
Society for the Promotion of Science KAKENHI Grant-in-Aid for
Scientific Research on Innovative Areas 25111005 (to N.M.)
and JP16H06280 (Resource and technical support platforms
for promoting research “Advanced Bioimaging Support”)
(to M.K.). The data are provided in the main manuscript
Materials and Methods
Figs S1 to S9
Movies S1 to S3
3 March 2016; resubmitted 16 July 2016
Accepted 10 October 2016
Published online 20 October 2016
Social status alters immune
regulation and response to infection
Noah Snyder-Mackler,1,2 Joaquín Sanz,3,4 Jordan N. Kohn,5 Jessica F. Brinkworth,3,6
Shauna Morrow,1 Amanda O. Shaver,1† Jean-Christophe Grenier,4 Roger Pique-Regi,7,8
Zachary P. Johnson,5,9‡ Mark E. Wilson,5,10 Luis B. Barreiro,4,11§|| Jenny Tung1,12,13,14§||
Social status is one of the strongest predictors of human disease risk and mortality, and
it also influences Darwinian fitness in social mammals more generally. To understand the
biological basis of these effects, we combined genomics with a social status manipulation
in female rhesus macaques to investigate how status alters immune function. We
demonstrate causal but largely plastic social status effects on immune cell proportions,
cell type–specific gene expression levels, and the gene expression response to immune
challenge. Further, we identify specific transcription factor signaling pathways that explain
these differences, including low-status–associated polarization of the Toll-like receptor
4 signaling pathway toward a proinflammatory response. Our findings provide insight into
the direct biological effects of social inequality on immune function, thus improving our
understanding of social gradients in health.
Many human societies exhibit social gra- dients in health (1). Socioeconomic status has been called the “fundamental cause” of health inequalities (2), and, in the United States, differences between the highest
versus lowest socioeconomic stratum may affect
adult life span by more than a decade (3). These
patterns arise, in part, from differences in resource
access and health risk behaviors. However, studies
in hierarchically organized animal species sug-
gest that they may also be more deeply embedded
in our evolutionary history (4). In rhesus macaques
and long-tailed macaques, social subordination
has been linked to changes in cardiovascular
health, hypothalamic-pituitary-adrenal axis func-
tion, inflammation, and gene expression in pe-
ripheral blood mononuclear cells (PBMCs) (5–7).
Such findings suggest strong parallels between
responses to social adversity in humans and
other social primates, especially in their conse-
quences for the regulation of the immune sys-
tem (8, 9).
We aimed to test how social status influences
immune system function at multiple scales, using
an experimental design that allowed us to infer
its direct causal effects. We experimentally manipulated the dominance ranks of 45 adult female
rhesus macaques, a species that naturally forms
stable, linear social hierarchies. In captivity, female
rank can be manipulated by sequential introduction of adult females into newly constructed social
groups, such that earlier introduction predicts
higher status (10) (measured here with continuous Elo ratings: a higher status corresponds
to a higher value) (11). We constructed nine groups
of five female macaques each (table S1). We maintained these groups for 1 year (phase one) (Fig. 1,
A and B) and then rearranged group composition
by performing sequential introduction of phase-one females from the same or adjacent ranks into
new groups, which we again followed for 1 year
Our study maximized within-individual changes
in dominance rank (Pearson’s correlation coefficient r = 0.06, P = 0.68 between phases) (fig.
S1), thus avoiding the possibility of confounding
rank effects on immune function with other
study-subject characteristics. In both phases, the
order of introduction predicted social status (phase
one Pearson’s r = –0.57, P = 4.1 × 10−5; phase two
r = –0.68, P = 3.3 × 10−7) (Fig. 1C), and social
status in turn influenced rates of received harassment (higher for low-status females) (Fig. 1D) and
affiliative grooming behavior (higher for high-status females) (Fig. 1E).
1Department of Evolutionary Anthropology, Duke University,
Durham, NC 27708, USA. 2Duke Center for the Study of
Aging and Human Development, Duke University, Durham,
NC 27708, USA. 3Department of Biochemistry, Faculty of
Medicine, Université de Montréal, Montréal, Quebec H3T1J4,
Canada. 4Department of Genetics, Centre Hospitalier
Universitaire Sainte-Justine Research Center, Montréal,
Quebec H3T1C5, Canada. 5Yerkes National Primate Research
Center, Emory University, Atlanta, GA 30322, USA.
6Department of Anthropology, University of Illinois at
Urbana–Champaign, Urbana, IL 61801, USA. 7Center for
Molecular Medicine and Genetics, Wayne State University,
Detroit, MI 48201, USA. 8Department of Obstetrics and
Gynecology, Wayne State University, Detroit, MI 48201, USA.
9Department of Human Genetics, Emory University School of
Medicine, Atlanta, GA 30322, USA. 10Department of
Psychiatry and Behavioral Sciences, Emory University School
of Medicine, Atlanta, GA 30322, USA. 11Department of
Pediatrics, Faculty of Medicine, Université de Montréal,
Montréal, Quebec H3T1J4, Canada. 12Department of Biology,
Duke University, Durham, NC 27708, USA. 13Institute of
Primate Research, National Museums of Kenya, Nairobi
00502, Kenya. 14Duke Population Research Institute, Duke
University, Durham, NC 27708, USA.
*These authors contributed equally to this work. †Present address:
Department of Genetics, University of Georgia, Athens, GA 30602,
USA. ‡Present address: Illumina, San Diego, CA 92122, USA.
§These authors contributed equally to this work. ||Corresponding
author. Email: email@example.com (J. T.); firstname.lastname@example.org (L.B.B.)