Nature 401, 1999, Charles R. Mackay, page 659
A newly identified chemokine receptor can identify two types of memory T cell with different migration preferences. Their existence may explain how memory cells initiate the rapid and effective secondary response to antigens.
Often, when a pathogen first infects the body, nothing happens - at least,
not for several days. But when the same pathogen is encountered a second time,
the response is rapid and vigorous. This phenomenon, known as immunological
memory, is the basis for vaccination, yet very little is understood about how
it protects the entire body so effectively. On page 34 of this supplement, Sallusto
et al.1 report that a newly identified cell-surface marker - the chemokine receptor
CCR7 - can distinguish two subsets of T cells that carry immunological memory.
These two subsets apparently circulate around the body by different pathways,
and mediate the memory response in different ways. The results provide a new
insight into the memory response, one that is relevant to basic immunology,
as well as to vaccination strategies and the development of immunosuppressive
therapies.
The immune system responds slowly to newly encountered pathogens owing to the
relative lack of antigen-specific cells. New pathogens must first be transported
to nearby lymphoid tissue, where the primary immune response develops and where
naive lymphocytes and antigen-presenting cells interact. Two clonally expanded
populations emanate from this primary response: 'effector' cells, which combat
spread of the pathogen; and 'memory' cells, which guard against subsequent infections.
Effector and memory cells are thought to be distributed to all tissues in the
body, particularly epithelial surfaces (such as the skin and gut) where pathogens
are likely to be re-encountered, so lymphocyte migration facilitates systemic
immunological memory.
How can we tell the difference between naive, memory and effector T cells? This
has been an elusive goal. In humans, isoforms of CD45 (a phosphatase involved
in cell signalling) seemed able to distinguish naive and memory T cells. Any
cell expressing the CD45RO isoform was regarded as a memory T cell, based on
the fact that CD45RO+ (memory) T cells - but not CD45RA+ (naive) T cells - can
respond vigorously in vitro to previously encountered antigens. Moreover, whereas
CD45RA+ T cells migrate almost exclusively through lymphoid tissue2, CD45RO+
T cells migrate throughout the body, including epithelial surfaces. The rationale
is that a naive T cell has such a low probability of seeing its specific antigen
that it needs to travel through the lymph nodes, which are designed for massive
migration of lymphocytes and antigen sampling2. In contrast, memory or effector
cells migrate mainly to peripheral tissues, providing protection at sites vulnerable
to challenge by pathogens. But the problem with this system was that both memory
and effector cells express CD45RO, so there was still no way to distinguish
between the two.
Sallusto et al.1 have now used a monoclonal antibody that recognizes the chemokine
receptor CCR7 to discriminate between the two subsets of CD45RO+ T cells. The
CCR7- subset has many characteristics of effector cells. For example, these
cells rapidly produce effector cytokines such as interferon-y, interleukin-4
and interleukin-5, or they express perforin granules (a feature of cytotoxic
cells). Cells in the CCR7+ subset, on the other hand, behave more like true
memory cells - they lack effector function, but the authors found that these
cells could differentiate to CCR7- effector cells after being stimulated with
antigen. So, expression of CCR7, in conjunction with CD45RO, distinguishes memory
cells from effector cells.
Many cells that migrate to the lymph nodes, such as naive T cells and antigen
presenting cells, express CCR7. Moreover, the chemokines that bind to CCR7 (MIP-3b
and secondary lymphoid chemokine; SLC) are both constitutively expressed in
lymph nodes. For example, SLC is produced by specialized blood vessels in the
lymph nodes and provides the entry cue for CCR7+ cells circulating in the blood3.
And the lymphocytes in mice that lack CCR7 or SLC migrate poorly through the
lymph nodes3,4. But CCR7 is only half the story, because cells first adhere
to the walls of the lymph-node vessels using a molecule called L-selectin. So,
the 'combination code' for entry of T cells to normal lymph nodes is L-selectin
binding, followed by CCR7 signalling through SLC. This code is expressed by
naive T cells and CCR7+ memory T cells (Fig. 1), but not by certain cells that
do not recirculate, such as neutrophils or monocytes. Trafficking experiments
show2,6 that a subset of memory T cells does indeed enter lymph nodes, although
we cannot yet say whether these are Sallusto and colleagues' CCR7+ memory T
cells.
The traffic of T cells through peripheral sites differs fundamentally from that
through lymph nodes. So-called 'inflammatory' chemokines and receptors are involved,
together with adhesion molecules that are upregulated by inflammatory cytokines.
The T cells recruited to peripheral tissues are usually very distinctive, and
include CD45RO+ T cells expressing chemokine receptors such as CCR5, CCR2 or
CCR3 (ref. 7). But Sallusto et al.1 show that these T cells, which are the effector-type
cells, do not express CCR7. CCR5 is a particularly good marker for a subset
of effector T cells, and T cells expressing CCR5 are prominent in inflammatory
disease and at mucosal surfaces7 (a feature that may relate to the transmission
of HIV-1). In fact, it is likely that the T cells that show a degree of tissue-selective
migration preferential migration through the skin, say, rather than the gut
- are effector-type T cells. For instance, the skin-homing subset of effector
T cells expresses cutaneous lymphocyte-associated antigen and the chemokine
receptor CCR4 (ref. 8).
The basis of immunological memory has long been contentious. According to one
theory, the long-lived, recirculating memory T cells differentiate quickly to
effector cells when they re-encounter an antigen. Another theory holds that
constant exposure to the antigen is needed to maintain memory. Sallusto and
colleagues now show that both CCR7' (memory) and CCR7- (effector) cells from
people immunized with tetanus toxoid respond well to subsequent challenge with
the toxoid in vitro. That is, toxoid-specific effector T cells remain alive
and well, years after an initial immunization. The implication is that immunological
memory is carried by both classical-type memory T cells (which Sallusto et al.
term central memory T cells, TCM) and effector T cells (now referred to as effector
memory T cells, TEM)2.
So what is the precursor-product relationship between the central memory T cell
and the 'effector' memory cell? Sallusto et al. propose that the naive T cell
differentiates to a central memory T cell and, finally, to an effector memory
cell. A more conventional idea is that effector cells are the precursors of
memory cells9. Whatever the case, the existence of two, types of memory cell
with different migration pathways makes a lot of sense. Effector memory cells
provide immediate front-line protection, particularly at epithelial surfaces.
The central memory cells are the reserves, which can differentiate rapidly to
effector memory cells in the lymph nodes in response to antigen. In conclusion,
Sallusto and colleagues' study illustrates an important principle - the relationship
between the functional activity of lymphocytes and their migration properties.
For this reason, the chemokine receptors are proving to be excellent markers
for various subsets of immune cells.
Charles R. Mackay is at the Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia.
1. Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Nature
401, 708-712 (1999).
2. Mackay, C. R. Adv. Immunol. 53,217-265 (1993).
3. Gunn, A D. et al. Proc. Natl Acad. Sci. USA 95, 258-263 (1998).
4. Gunn, M. D. et al. 1. Exp. Med. 189, 451-460 (1999).
5. Förster, R. et al. Cell 99, 23-33 (1999).
6. Williams, M. B. & Butcher, E. C. J. Immunol. 159,1746-1752 (1997).
7. Sallusto, F., Lanzavecchia, A. & Mackay, C. R. Immunol. Today 19, 568-574
(1998).
8. Campbell, J. et al. Nature 400, 776-780 (1999).
9. Jacob, J. & Baltimore, D. Nature 399, 593-597 (1999).