another selective process occurs long before, in early life, and this other process
is the elimination of immune cells that recognize“self”components (Burnet
1959). This explains why, in 1969, Burnet writes that the clonal selection theory
provides“the simplest possible interpretation of how the body’s own constitu-
ents are shielded from immunological attack”(Burnet 1969, p. 12).
From the second half of the twentieth century to the present day, the self–
nonself framework has been adopted by a large majority of immunologists and
enriched by a host of experimental, conceptual, and theoretical contributions
(e.g.,Bretscher and Cohn 1970; von Boehmer and Kisielow 1990; Janeway
1992; Langman and Cohn 2000). Today, the self–nonself remains the dominant,
if often implicit, framework in which immunologists conceive how the immune
system works (e.g.,Stefanová et al. 2002; Goodnow et al. 2005; Jiang and Chess
2009; Fulton et al. 2015). This is particularly illustrated by the fact that when
a novel immune system is identified, as recently happened with the CRISPR-
Cas systems in archaea and bacteria, scientists spontaneously use the self–
nonself vocabulary to account for its functioning (Nuñez et al. 2015) (this
comes in addition to the idea of CRISPR-Cas as a system ofdefense,as
discussed in the previous section). Together with the persistent use of the
self–nonself vocabulary in several other domains (including, for instance,
studies on autoimmune diseases and transplantation), this confirms the long-
standing influence of this framework in immunology over the last six decades.
3.2 Autoimmunity, Tolerance, and Symbiotic
Interactions with Microbes
Despite its undeniable success as an encompassing conceptual framework for
immunology, the self–nonself theory faces many difficulties. First, far from
being always pathological, autoimmunity has been proved to be a necessary
component of everyday immunity. A degree of autoreactivity (i.e., reaction to
“self”) characterizes the lymphocytes generated and selected in primary lym-
phoid organs as well as naïve lymphocytes circulating in the periphery (Tanchot
et al. 1997; Anderton and Wraith 2002; Hogquist and Jameson 2014). Effector
T cells are selected only if they react weakly to self elements (and not if they do
not react at all). Moreover, strong autoreactivity in the thymus can lead to the
selection and differentiation of lineages specific to self elements, including
regulatory T cells (cells that dampen the activation of the immune system and
play a key role in the prevention of autoimmune diseases) (Wing and Sakaguchi
2010). In addition, many effector immune responses that occur routinely at the
periphery during the lifetime of an organism target endogenous (“self”) ele-
ments, as illustrated by the phagocytosis of dead cells, the clearance of cellular
Philosophy of Immunology 17