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responses could also form against patho-

gens, as proposed for NK cells in response

to viral infections ( 2 ).

Macrophages are heterogeneous tissue-

resident cells: Yolk sac– and fetal liver

monocyte–derived tissue-resident macro-

phages colonize different tissues during

embryonic development ( 11 ). These are

long-lived and able to self-renew, so the

specific characteristics of these macro-

phages rely on their niche ( 11 ). For example,

lung macrophages are exposed to airway

antigens, whereas Kupffer cells in the liver

are exposed to gut-derived molecules ( 12 ).

The phenotype of a microglial cell in the

brain greatly differs from that of a perito-

neal macrophage ( 11 ). The potential ability

of these and other myeloid cell subsets to

develop different types of immunological

memory to antigens could offer additional

evidence for their different functions across

tissues and help to explain the development

of different types of memory responses to

the same antigens in different locations. In

this context, it will be crucial to address if

the antigen-specific responses by myeloid

cells can also be inhibitory and may be in-

volved in the development of immunologi-

cal tolerance leading to the lack of respon-

siveness against harmless molecules such as

antigens expressed by commensal bacteria,

or self-antigens. Immunological tolerance

prevents harmful immune responses in the

host, whereas failure of these mechanisms

results in tissue damage and autoimmune

responses ( 13 ). Indeed, polymorphisms

in genes of the human leukocyte antigen

(HLA) system, the human version of MHC,

are associated with celiac disease, inflam-

matory bowel disease, rheumatoid arthri-

tis, psoriasis, type 1 diabetes, and multiple

sclerosis ( 14 , 15 ). Additional studies have

found genetic associations between MHC-I

and infectious diseases such as HIV, human

hepatitis B virus, and tuberculosis ( 14 ).

If monocytes and macrophages develop

antigen-specific memory to antigens pre-

sented by donor-derived MHC-I molecules,

it is likely that these and other myeloid cells

can develop immunological memory to

self- and nonself antigens of different

sources. Given the variety of receptors ex-

pressed by the different types of myeloid

cells, the implications of these mechanisms

could encompass many processes beyond

organ transplantation, including the re-

sponse to pathogens, vaccines, inflamma-

tory and autoimmune diseases, or the de-

velopment of allergies. Dai et al. identified

several families of polymorphic Ig super-

family receptors that could bind to MHC-I

molecules. The extension of this search to

other receptors that can bind antigens of a

different nature could lead to the identifica-

tion of other structures with the potential

to trigger or block antigen-specific memory

in myeloid cells, potentially offering a new

set of targets for immunotherapy.

REFERENCES AND NOTES

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2. M. G. Netea et al., Nat. Rev. Immunol. 1 0. 1 0 3 8 /s 4 1 5 7 7-
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3. L. C. J. de Bree et al., Semin. Immunol. 39 , 35 (2018).


4. H. Dai et al., Science 368 , 1122 (2020).


5. F. L. Watson et al., Science 309 , 1874 (2005).


6. S. M. Zhang, C. M. Adema, T. B. Kepler, E. S. Loker, Science
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7. L. Du Pasquier, Science 309 , 1826 (2005).


8. M. G. Netea, A. Schlitzer, K. Placek, L. A. B. Joosten, J. L.
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9. S.-C. Cheng et al., Science 345 , 1250684 (2014).


10. E. Kaufmann et al., Cell 172 , 176 (2018).


11. M. Guilliams, G. R. Thierry, J. Bonnardel, M. Bajenoff,
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12. A. J. Macpherson, M. Heikenwalder, S. C. Ganal-
    Vonarburg, Cell Host Microbe 20 , 561 (2016).


13. J. A. Bluestone, Immunol. Rev. 241 , 5 (2011).


14. V. Matzaraki, V. Kumar, C. Wijmenga, A. Zhernakova,
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ACKNOWLEDGMENTS

M.G.N. is supported by a European Research Council

Advanced Grant (no. 833247) and a Spinoza Grant.

10.1126/science.abc2660

Resting Activation Development of memory Memory response

Monocytes

Macrophages

Epigenetic

changes

Trained immunity

Specifc innate

immune memory

PIR-A MHC-I specifcity

Second

stimulus

Cytokines

Cytokines

First

stimulus

DEVELOPMENT

Testicular-borne

factors affect

sperm fertility

Immature testicular germ

cells secrete factors that

influence sperm maturation

in mice

By Te s s a L o r d^1 and Jon M. Oatley^2

M

ale fertility relies on the genesis of

sperm in seminiferous tubules of

the testis and their maturation dur-

ing transit through the epididymis.

Mouse models with impaired devel-

opment of the most proximal region

of the epididymis, the initial segment (IS),

possess sperm that are morphologically nor-

mal but incapable of fertilizing an egg ( 1 ). It

has been postulated that factors synthesized

in the testis are released into the lumen of tu-

bules (lumicrine factors) and influence devel-

opment and function of the IS. However, the

identity of such factors has remained elusive.

On page 1132 of this issue, Kiyozumi et al.

( 2 ) identify and characterize the first known

lumicrine factor, the germ cell–secreted pro-

tein neural epidermal growth factor–like like

2 (NELL2). They demonstrate a key role for

NELL2 in driving development of the IS of

mice, culminating in the production of IS-

secreted proteases that are indispensable for

sperm processing in the epididymis and thus

male fertility.

The epididymis is a convoluted ductal sys-

tem of up to 1 m in length in mice and 6 m

in humans. Testicular sperm must transit the

length of the epididymis to gain the capacity

for fertilization, including activation of the

machinery that drives motility as well as egg

recognition and binding. Given that sperma-

tozoa are transcriptionally and translation-

ally silent, the process of sperm maturation

is largely attributed to activities of epididy-

mal epithelial cells, which can include post-

translational modification, augmentation,

and processing of sperm proteins. Proteomic

comparisons of sperm collected from the

more proximal regions of the epididymis

(^1) Priority Research Centre for Reproductive Science,
Discipline of Biological Sciences, the University of Newcastle,
Callaghan, NSW, Australia.^2 Center for Reproductive
Biology, School of Molecular Biosciences, Washington State
University, Pullman, WA, USA. Email: [email protected]
Different forms of innate immunological memory
Some myeloid cells can develop memory. After a first stimulus, retained epigenetic changes can facilitate
the production of cytokines after a nonspecific stimulus (trained immunity). Macrophages can also develop
specific memory through paired immunoglobulin-like receptor-A (PIR-A) specificity to antigens presented by
major histocompatibility complex class I (MHC-I).
5 JUNE 2020 • VOL 368 ISSUE 6495 1053
Published by AAAS