OPINION ARTICLE
published:28August2014
doi:10.3389/fimmu.2014.00411 Revisiting thymus function
Jacques F.A.P.Miller*
Department of Immunology,Walter and Eliza Hall Institute of Medical Research,Parkville,VIC,Australia
*Correspondence:***************.au
Edited by:
Nick Gascoigne,National University of Singapore,Singapore
Reviewed by:
Charles Surh,The Scripps Research Institute,USA
Nick Gascoigne,National University of Singapore,Singapore
Keywords:thymus,thymic-dependent lymphocytes,adaptive immunity,cellular immunity,neonatal thymic function
For centuries,the thymus has been an organ in search of a function.The fact that it is a large mass of tissue in infancy was not appreciated at the beginning of the twentieth Century,as autopsies per-formed in infants succumbing to fatal ill-nesses such as diphtheria,revealed a small thymus.This resulted from stress during the illness,but the small size of the thy-mus was thought to be the norm.When infant death occurred during anesthesia for stress-unrelated conditions,fatality was blamed not on the anesthetic but on the large thymus.Some doctors even pre-scribed radiation therapy to shrink the thy-mus(1),not realizing that some of their patients would later develop adenocarci-noma of the thyroid.
Prior to1961,the thymus was con-sidered not to have any role in immu-nity.The major reasons for this can be summed up as follows.Unlike lympho-cytes obtained by thoracic duct cannu-lation or from spleen and lymph nodes, thymus lymphocytes were generally poor in their ability to initiate immune reac-tions after adoptive transfer to appropri-ate recipients.Thoracic duct lymphocytes could
home from blood into lymphoid tis-sues,“the only exception”being“the thy-mus in which very few small lymphocytes”appeared“to lodge”(2).The production of antibody-forming plasma cells and the for-mation of germinal centers,so prominent in spleen and lymph nodes,were not seen in thymus tissue of normal or immunized animals.Defects in immune responsive-ness had never been documented in mice whose thymuses had been removed dur-ing adult life,a fact that had led some groups to conclude that“the thymus gland does not participate in the control of the immune response”(3).At a Symposium on Cellular Aspects of Immunity(4),in
which took part world-renowned immu-
nologists including Burnet,Good,Leder-
berg,Medawar,and Mitchison,and pub-
lished in1960,not a single reference was
made to the thymus or to its cells through-
out the meeting.Immunologists believed
that,as a predominantly epithelial organ,
the thymus had become vestigial during
evolution and was just a graveyard for
dying lymphocytes.Medawar even stated,
“We shall come the regard the presence of
lymphocytes in the thymus as an evolu-
tionary accident of no very great signifi-
cance”(5).
In the late1950s,I was working on
mice with lymphocytic leukemia that was
induced in low-leukemic strain mice[as
demonstrated by Ludwik Gross(6)]by
injectingfiltered extracts of leukemic tis-
sues obtained from high leukemic strain
mice.A leukemogenic virus was believed
to be the causative agent and it had to be
given to newborn mice to obtain a high
incidence of leukemia.The disease began
in the thymus and thymectomy at1month
of age prevented its onset(7).Grafting a
neonatal thymus6months after thymec-
tomy restored the potential for leukemia
development(8),and the virus could be
recovered from the non-leukemic tissues
of thymectomized mice(9).But why did
it have to be given at birth?One possibility
was that it could multiply only in neona-
tal thymus and would then spread to other
sites.To test this,mice were thymectomized
before the virus was given and therefore at
birth.
The survivors grew well atfirst but,after
weaning,many wasted and died prema-
turely whether inoculated with virus or
not.Adult thymectomy,on the other hand,
had never shown any untoward effects
such as weight loss or obvious pathology.
This led me to conclude“that the thy-
mus at birth may be essential to life”(10).
Histological examination of the tissues of
neonatally thymectomized mice revealed a
marked deficiency of lymphocytes in the
circulation and the lymphoid tissues and
many wasted mice had liver lesions sug-
gesting infection by some hepatitis virus
(11,12).At that time Gowans had shown
that small lymphocytes were not short
lived cells,as had been thought before,
but immunologically competent cells with
a long lifespan,recirculating from blood
through lymphoid tissues into lymph and
able to initiate immunological reactions
when appropriately stimulated by anti-
gen(13).Clearly,my neonatally thymec-
tomized mice must have been immunod-
eficient,which accounted for their sus-
ceptibility to virus infections.I therefore
tested their immune competence by graft-
ing skin from allogeneic mice and from
rats.The results were incredibly spectac-
ular and publishedfirst in The Lancet
in1961(11)and in greater detail in the
Proc Roy Soc.(12).The mice failed to
reject skin both from totally unrelated
strains(“H-2-incompatible”)and from
rats,and failed to do so even when grafted
before the onset of wasting.Since both
Gowans and Medawar hadfirmly estab-
lished that rejection of foreign skin grafts
was mediated by lymphocytes,and since
my mice were deficient in lymphocytes fol-
lowing neonatal thymectomy,it was log-
ical for me to conclude that the thymus
was the source of immunologically com-
petent lymphocytes,at least during the
neonatal period.Contrary to the prevail-
ing opinion,I postulated“during embryo-
genesis the thymus would produce the
originators of immunologically competent
cells many of which would have migrated to other sites at about the time of birth. This would suggest that lymphocytes leav-ing the thymus are specially selected cells”(11).I had therefore proposed the bold postulate that the thymus was the site responsible for the development of immunologically competent small lym-phocytes.
The few neonatally thymectomized mice that did eventually reject allogeneic skin grafts were later grafted again with skin from the same donors but showed no evi-dence of a second set response(12).By con-trast,neonatally thymectomized mice bear-ing well-established allogeneic skin rejected that skin rapidly when given intravenous lymphocytes from normal donors that had been immunized to skin of the same strain(12).
I tested the ability of my neonatally thymectomized mice to produce antibody to Salmonella typhi H antigen and found this to be impaired(12).
Grafting thymus tissue to neonatally thymectomized mice prevented immuno-logical deficiency.Although implantation of syngeneic thymus tissue allowed these mice to develop a normal immune sys-tem,grafting a thymus derived from a for-eign strain induced specific immune toler-ance
to the histocompatibility antigens of the donor.Thus,lymphocytes developing in the thymus in the presence of foreign cells must have been ,“selec-tively thymectomized”as I suggested(12)]. Hence,by implication,the thymus should be the site where self tolerance is imposed and where discrimination between self and non-self takes place.
Showing that cells from the thymus migrated into the lymphoid tissues was dif-ficult at that time,since no markers had been found to identify cells from different locations.So I made use of the T6mouse strain the cells of which could easily be identified at metaphase by the presence of 2min chromosomes.Neonatally thymec-tomized F1hybrid mice in which one par-ent was T6,were grafted with thymus from the other parental strain and immunized with skin from various donors.An analy-sis of the chromosome constitution of the cells in metaphase in the spleen showed that 15–20%had originated from the thymus graft(12).
My conclusions concerning the
immunological function of the thymus
were regarded with skepticism by the
immunological community.For exam-
ple,Medawar was not convinced as evident
from a letter he sent to me in which he
wrote:“I take it that the thymic tissue seen
infishes is wholly or predominantly epithe-
lial,as its phylogenetic origin suggests.It
is a matter of some interest that many
organs,which seem to become redundant
in the course of evolution undergo a sort of
lymphocytic transformation”(14).Trivial
criticisms abounded:what I had observed
must surely have occurred only in the
strain of mice that I had been using;my
mice must have been in such poor health
that any surgical trauma would prejudice
their ability to reject skin grafts;whatever
the thymus might have been doing in my
mice,it could not possibly do in humans!
At a Ciba Foundation Symposium on
Tumor Viruses of Murine Origin held in
Perugia in June1961,thefirst international
meeting where I presented my results,
R.J.C.Harris,claimed the following:“Dr.
Delphine Parrott in our laboratory has
been thymectomizing day-old mice and
there is at present no evidence that these
animals are immunologically weaker than
normal animals.They do not retain skin
grafts;they are living and breeding quite
normally.They do not die of laboratory
infections”(15).
These criticisms did not last very long
as I and several other researchers repeated,
confirmed,and extended my results.It was
evident,for example,that the adult thymus
would still play a role in immunogenesis
and this was shown when the rest of the
lymphoid system was destroyed by total
body irradiation and the mouse protected
by an injection of bone marrow(16,17).
The adult thymectomized irradiated and
marrow protected mice were crucial to our
subsequent demonstration of the existence
of two major lymphocyte subsets,T and B
cells(18).An avalanche of work followed
these early investigations.
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Conflict of Interest Statement:The author declares that the research was conducted in the absence o
thyme
f any commercial orfinancial relationships that could be construed as a potential conflict of interest. Received:16July2014;accepted:13August2014; published online:28August2014.Citation:Miller JFAP(2014)Revisiting thy-
mus function.Front.Immunol.5:411.doi:
10.3389/fimmu.2014.00411
This article was submitted to T Cell Biology,a section of
the journal Frontiers in Immunology.
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