A Fagraeus

A Radbruch

Andreas Radbruch

E Behring Von

K Tokoyoda

MK Slifka

RA Manz

English

PubMed

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INTRODUCTION
Memory on the move
Andreas Radbruch
Received: 10 March 2012 / Revised: 13 March 2012 / Accepted: 13 March 2012 / Published online: 6 April 2012
 The Author(s) 2012. This article is published with open access at Springerlink.com
Immunological memory, next to specificity and tolerance,
can be regarded as one of the key characteristics of the
adaptive immune system, adapting it to the antigenic
challenges and pathogens of its environment. Knowledge
about the acquisition of ‘‘Immunity’’ to recurrent patho-
gens is cultural heritage of mankind. The Greek writer
Thucydides in 400 B.C. mentions it in his chronicles as
established knowledge [1]. This knowledge has also been
exploited early on, ‘‘inoculating’’ children with attenuated
pathogens, a custom that reached Europe from Asia, as
discussed by Voltaire in 1733 [2], and later marketed as
‘‘vaccination’’ according to Jenner in 1798 [3].
When Behring and Kitasato demonstrated the specific
protection of rabbits by serum from infected animals in
1890 [4], it became clear that serum antibodies could
provide ‘‘immunity’’, i.e., protection against a recurrent
infectious challenge. It took another 60 years until Astrid
Fagreus discovered the cells secreting those antibodies, the
‘‘plasma cells’’, describing them as ‘‘terminal stages of B
cell differentiation’’ [5]. ‘‘Protective memory’’, as provided
by serum antibodies, was later conceptually complemented
by a ‘‘reactive memory’’ formed by expanded and long-
lived populations of antigen-experienced T and B
lymphocytes.
The nature of this reactive memory and its role in
‘‘immunity’’ is a matter of debate even today. The nature of
‘‘protective memory’’ became less controversial recently,
since it has been shown in the past 15 years that plasma
cells can survive as ‘‘memory’’ plasma cells in the bone
marrow, secondary lymphoid organs and inflamed tissues,
in dedicated ‘‘survival niches’’ organized by specialized
stromal cells [6–9]. This concept, challenging the tradi-
tional view of long-lived effector cells and/or memory cells
with a ‘‘halflife’’ and ‘‘homeostatic’’ regeneration of
memory, emerged when analyzing the lifestyle of long-
lived plasma cells. Could it be a general principle of the
organization of memory? Tracking T helper cells through
the immune reaction, to protein antigens mimicking vac-
cines, into the ‘‘memory phase’’ surprisingly showed that
while the cells gradually disappeared from the periphery,
about 20 % of them were stably maintained alive in the
bone marrow in niches similar to those of the plasma cells
but definitely organized by different stromal cells [10]. The
T helper cells from bone marrow were resting in terms of
transcription and proliferation, but highly reactive to
restimulation and potent helpers of activated B cells. These
cells pose an immense challenge to the traditional views on
‘‘reactive memory’’. Antigen-experienced T helper, cyto-
toxic T cells and B cells are present in the periphery, they
can be long-lived, they are functionally diverse, and they
can provide protection upon adoptive transfer. What is their
role as compared to the resting bone marrow cells? How
are the T cells of bone marrow reactivated upon antigenic
challenge? Are cytotoxic T cells and B cells also resting in
the bone marrow? In short: Analysis of immunological
memory is on the move! It is at this break that we here
assemble the viewpoints of eminent scientists who have
contributed key concepts to our current views an immu-
nological memory.
In the first essay, Zehn and colleagues discuss how the
original activation of T cells by antigen impacts their
activation and development into long-lived cells. Yamane
and Paul then provide a look into the T cells themselves, in
particular their functional polarization and imprinting, and
A. Radbruch (&)
Deutsches German Rheumatism Research Centre (DRFZ)
Berlin, an institute of the Leibniz Association, Berlin, Germany
e-mail: radbruch@drfz.de
URL: http:\\www.drfz.de
Cell. Mol. Life Sci. (2012) 69:1563–1564
DOI 10.1007/s00018-012-0964-y Cellular and Molecular Life Sciences
123
their developmental plasticity. This is also discussed by
Buchholz and colleagues, for CD8? T cells, in particular
with respect to the question whether effector and memory
cells are distinct lineages or not?
Boyman and colleagues then discuss the maintenance of
long-lived T cell and NK cell populations of the periphery
by ‘‘homeostatic’’ proliferation, in the apparent absence of
antigen. The recently identified memory T helper cells
from bone marrow, described by Tokoyoda and Radbruch,
are resting in terms of proliferation. While we poorly
understand their relation to peripheral effector memory
cells, they provide a new model of organization and
maintenance of memory by stromal cells. This may be a
general principle of organization of memory, since it has
recently been shown that also long-lived memory plasma
cells are organized by bone marrow stromal cells. In a final
view on T cell memory, Goronzy and Weyand draw our
attention to the aging memory and its potential for a break
of tolerance and induction of autoimmune diseases.
The discourse is closed by two provocative essays.
Reynaud and colleagues discuss B cell memory, in par-
ticular the controversial facet of IgM memory B cells,
which are a remarkable population in humans, and not so in
mice. This raises the general question of how to model
long-lasting memory in short-lived mice. Not to forget the
memento of Rolf Zinkernagel, to put memory in its bio-
logical context, and to understand it with respect to its
protective value, which brings us back to Thucydides.
Open Access This article is distributed under the terms of the
Creative Commons Attribution License which permits any use,
distribution, and reproduction in any medium, provided the original
author(s) and the source are credited.
References
1. Thucydides The history of the Peloponnesian war (Vols. I and II
C.F. Smith, trans.) 1919 and 1921, Harvard University Press
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2. Franc¸ois Marie Arouet de Voltaire (1910) Letters on the English:
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1564 A. Radbruch
123


Memory on the move

Crossref

Cellular and Molecular Life Sciences

(1798) An inquiry into the causes and effects of the variola vaccinae, or cow pox. In:

Fagraeus A

Franc ¸ois Marie Arouet de Voltaire

Mar) Humoral immunity due to long-lived plasma cells.

Oct) Competence and competition: the challenge of becoming a long-lived plasma cell.

Radbruch A

Thucydides The history of the Peloponnesian war (Vols. I and II

https://link.springer.com/content/pdf/10.1007%2Fs00018-012-0964-y.pdf

Memory on the move

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