The n e w e ng l a n d j o u r na l of m e dic i n e

Cl inic a l I m pl ic a t ions of B a sic R e se a rch

Elizabeth G. Phimister, Ph.D., Editor

The Immune Response Learning to Leave Well Enough Alone

James T. Rosenbaum, M.D.

The immune system in the body walks a tight- nize danger, it must also devise ways to ensure
rope. It must recognize millions of potential that it does not attack targets that could result
danger signals. But having devised ways to recog- in self-harm. For the most part, it succeeds ad-
mirably; occasionally it makes a faux pas, and
rheumatoid arthritis, systemic lupus erythemato-
Thymic Deletion Intestinal Deletion
sus, and Graves disease are some of the results.
To avoid an attack against itself, the epithelium
of the thymus displays self-antigens to T lympho-
cytes and deletes those that have the potential
to cause autoimmune disease (Fig. 1). Other
checks and balances such as regulatory T cells
are also in place, but the thymus has, arguably,
the major role.
Learning to ignore self-antigens is only part
Thymic Autoreactive Innate Bacteria-reactive of the challenge; the immune system must also
epithelial cell CD4 T cell lymphoid 3 cell CD4 T cell
learn to be accepting of certain foreign antigens
Auto-
antigen
Bacterial
antigen
as well. Indeed, this is an essential obligation of
the immune system. Imagine the consequences
of lymphocytes doing continuous battle against
MHC T-cell bacteria in the mouth, skin, or intestine. How
MHC T-cell
class II receptor class II receptor does the immune system educate lymphocytes to
adopt a laissez-faire attitude toward nonpatho-
genic bacteria? In a recent publication,1 Hepworth
and colleagues describe a mechanism that has
major implications for the understanding of in-
flammatory bowel disease.
Apoptosis Autoimmunity Apoptosis Autoinflammation
The immune system is usually conceptualized
as having two divisions: an innate response and
Figure 1. Autoimmunity and Autoinflammation. an adaptive response. The innate division includes
The thymus is responsible for deleting autoreactive T cells that have the neutrophils and macrophages. Cells in the innate
potential to cause autoimmune disease. Medullary epithelial cells or den- division have receptors to recognize microbial
dritic cells in the thymus present antigen in association with a cell-surface products. The innate division can respond rapid-
molecule known as MHC class II. The antigen is recognized by the T-cell
ly but rather indiscriminately to a danger signal.
receptor. If the recognition is strong, the autoreactive T cell is killed by
means of apoptosis. The failure to delete autoreactive cells potentially re- In contrast, the adaptive division, which includes
sults in autoimmunity. ILC3 cells (a subset of innate lymphoid cells) in the T and B lymphocytes, can rearrange genes such
lamina propria of the intestine or in the mesenteric lymph node perform a as immunoglobulins or antigen receptors and
similar function, except that the T cells that are deleted are those that recog- thus achieve a highly targeted, precise response.
nize bacterial antigens and could thus cause inflammatory bowel disease.
This process takes time, so although it is
As in the thymus, the ILC3 cells use MHC class II to present antigen to T cells.
If a bacterial antigen is presented and strongly recognized by the T cell, the more selective the adaptive division is slower
T cell undergoes apoptosis. The failure to delete these cells results in inflam- to offer protection.
mation that can be labeled autoinflammatory. To parse the human immune system into two
divisions, however, is to simplify. The immune

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 Clinical Implications of Basic Research
system also has cells that incorporate aspects of
both the innate division and the adaptive one.
The cells look like lymphocytes. They have been
dubbed innate lymphoid cells to signify how
they straddle the two systems. Unlike the lym-
phocytes in the adaptive immune system, these
cells cannot perform gene rearrangements of
their antigen receptors. Innate lymphoid cells
are vastly outnumbered by conventional lympho-
cytes, but they have been implicated in an array
of diseases, especially ones involving mucosal
surfaces such as skin, gut, or lung.2
Hepworth and colleagues engineered mice
with an impairment of a subset of innate lym-
phoid cells called ILC3 cells.3 The ability to bio-
engineer these mice relies on the recognition
that ILC3 cells are unique in their expression of
several specific genes. Using a well-established
genetic engineering system, they deleted a gene
encoding a critical component of MHC2 in ILC3
cells. MHC class II presents antigen that is recog-
nized by CD4 T lymphocytes.
Crohns disease and ulcerative colitis are
characterized by a dysbiosis, meaning a change
in the microbiome, the bacteria that colonize the
gut. In persons with Crohns disease, CD4 lym-
phocytes, which in healthy persons ignore bac-
teria in the intestine, have an exuberant immune
response that correlates with bowel inflamma-
tion and disease. Since inflammatory bowel dis-
ease is not the result of an attack against self-
antigens, it should not be called autoimmune.
Some have proposed that autoinflammatory is a
more appropriate label.4
In mice that lack ILC3-intrinsic MHC class II,
bowel inflammation that resembles Crohns
disease develops. Hepworth and colleagues
found that these mice have an excess of lympho-
cytes that recognize bacterial antigens. In con-
trast, T lymphocytes that recognize nonbacterial
antigen appear to be unaffected, as do regula-
tory T cells. Amazingly, the ILC3 cells function
much like the epithelium in the thymus (Fig.1).
These cells can present antigen in a way that is
analogous to the way that a dendritic cell acti-
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The New England Journal of Medicine
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vates a T cell to make a specific response. But
the ILC3 cells lack the accessory molecules that
are necessary for the activation to occur. Instead
of activation, the ILC3 cells residing in the
lamina propria of the bowel and in the mesen-
teric lymph nodes selectively kill lymphocytes
that are capable of responding to bacterial anti-
gen originating from the gut. Just as thymic
epithelium prevents autoimmunity, ILC3 cells
prevent autoinflammatory disease in the bowel.
Although this observation alone provides a
leap in the understanding of the regulation of
the immune response, the authors extended
their work by analyzing intestinal-biopsy speci-
mens from children with Crohns disease. The
biopsies revealed a deficiency in the expression
of ILC3-intrinsic MHC class II, which suggests
that the pathogenesis of the disease in humans
might mimic that of the mouse model. Potentia-
tion of the ILC3 response in the gut as might be
achieved by cytokines, growth factors, or even
transfusion of autologous ILC3 cells after culture
in vitro represents a potential strategy for the
treatment of inflammatory bowel diseases. Just
as it is critical to learn how our immune system
can recognize a foreign antigen, it is equally
important to understand how the immune sys-
tem learns to leave well enough alone.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
I thank Mark Asquith for comments on an earlier version of
the manuscript.
From the Casey Eye Institute and the Legacy Devers Eye Insti-
tute both in Portland, OR.
1. Hepworth MR, Fung TC, Masur SH, et al. Immune tolerance:
group 3 innate lymphoid cells mediate intestinal selection of com-
mensal bacteria-specific CD4+ T cells. Science 2015;348:1031-5.
2. Sonnenberg GF, Artis D. Innate lymphoid cells in the initia-
tion, regulation and resolution of inflammation. Nat Med 2015;
21:698-708.
3. Hepworth MR, Monticelli LA, Fung TC, et al. Innate lym-
phoid cells regulate CD4+ T-cell responses to intestinal com-
mensal bacteria. Nature 2013;498:113-7.
4. McGonagle D, McDermott MF. A proposed classification of
the immunological diseases. PLoS Med 2006;3(8):e297.
DOI: 10.1056/NEJMcibr1511284
Copyright 2015 Massachusetts Medical Society.
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