Cytokines and the Immune System

4 Pages·0.057 MB·English

by  Durum S.K.

Cytokines and the
Immune System
Scott K. Durum
*
Laboratory of Molecular Immunoregulation, National Cancer Institute, FCRDC, DBS Building,
Room 31-73, Frederick, MD 21702-1201, USA
*corresponding author tel: [phone], fax: [phone], e-mail: [email protected]
DOI: 10.1006/rwcy.2000.02001.
SUMMARY An early controversy among immunologists in the
1970s concerned the mechanism by which T cells
helped B cells to produce antibody, some immunol-
Cytokines are important signaling molecules in the
ogistsfavoringcytokines,othersfavoringcellcontact.
immune system. The immune processes controlled by
Now that a number of the mechanisms are under-
cytokines will be introduced in this overview, which
stood at the molecular level, the distinction between
covers molecules termed ‘immunomodulatory cyto-
cell-bound and secreted molecules has become some-
kines’ in this database as well as other cytokines and
what blurred. Many of the integral membrane
peptide hormones. The immune response is modu-
molecules (like CD40L) are actually very similar to
lated by cytokines that affect cell proliferation (IL-2,
released molecules (like TNF). Moreover, many of
IL-4, growth hormone, TGF(cid:12), and many others),
the secreted cytokines (like chemokines, TGF(cid:12), and
survival (IL-7, prolactin, FasL), differentiation (IL-4,
IL-7) are probably not actually recognized in their
IL-12),antigenpresentation(GM-CSF,IFN(cid:13),IL-10)
soluble forms, but rather in a form attached to other
andtrafficking(chemokines).Inadditiontothedirect
membranes and extracellular matrix.
effects of cytokines on mature cells of the immune
Early immunological studies identified soluble
system, the development of immune cells depends on
activities made by lymphocytes or acting upon
cytokines(IL-7,SCF,Flt-3L,SDF,IL-15)asdoesthe
lymphocytes (the earlier term ‘lymphokine’ has been
architectureoflymphoidorgans(LT,TNF).Cytokines
supplanted by the broader term ‘cytokine’). The
link the immune system with the inflammatory res-
activitiesincludedproliferationofTcells,Bcells,and
ponse(IL-1,IL-6,TNF)andwiththecentralnervous
thymocytes,inductionofIgsecretion,cytotoxicTcell
system (growth hormone, prolactin, IL-1). Viruses
generation, cell death, macrophage activation, and a
produce a number of agents that combat cytokine
host of other immune and inflammatory responses.
pathways (IFN, TNF, IL-1, chemokines) or suppress
The ability to clone cytokines has greatly moved
(IL-10) processes involved in antiviral immunity.
research, and the production of knockout mice has
placed each cytokine in a physiological perspective.
This chapter will outline the general types of immu-
BACKGROUND
nological processes regulated by the cytokines, refer-
ring the reader to individual chapters for in-depth
The immune response to foreign antigens is based on treatments and bibliographies.
the remarkable activities of a rather small number of
lymphocytes that specifically recognize each antigen.
LYMPHOID DEVELOPMENT
Theimmuneresponseculminatesintheeliminationof
these antigens using an armamentarium of immuno-
globulins, cytolytic T cells, and recruited inflamma- T cell development in the thymus requires several
tory cells that engulf the invaders. cytokines. IL-7 is required for pro-T cells to survive
96 Scott K. Durum
andrearrangethegenesencodingsomeoftheantigen induce the switch to different isotypes. IL-4 or IL-13
receptors.TSLP,anIL-7homolog,alsohasactivities. induce switch to IgE and IgG1, IFN(cid:13) induces switch
SCF and Flt-3 ligand are involved in proliferation to IgG2a and IgG3, and TGF(cid:12) induces switching to
and survival of early thymocyte stages. Negative IgA. All switching requires CD40L. IL-2, IL-10, and
selection of intermediate thymocyte stages is partly IL-15 also promote Ig production, whereas TGF(cid:12)
mediatedbyFasL andCD30L.Bcell developmentin inhibits Ig secretion. Memory B cell development is
bonemarrowdependsonthechemokineSDF.Inmice induced by CD40L.
(butnothumans)Bcelldevelopmentalsodependson
IL-7. TSLP appears to promote early B cell dev-
elopmental stages. Large granular lymphocytes (NK
ANTIGEN-PRESENTING CELLS
cells) require IL-15 for development. In all these
cases,otherstromalcellsurfacemolecules,inaddition
to the secreted cytokines, are required. The activation of T cells is dependent on antigen-
presenting cells (APCs) which in turn depend on
cytokines to induce their differentiation from pre-
cursorstobecomeactiveAPCs.Thedevelopmentand
LYMPHOID PROLIFERATION
APC function of dendritic cells has been induced by
AND SURVIVAL various cocktails of cytokines that have incorporated
GM-CSF, TNF, TGF(cid:12), CD40L, IL-1, and IL-4.
Macrophage APC function is enhanced by IFN(cid:13)
Activated T cells proliferate in response to IL-2 or to
whichincreasesthe levelsofMHCand peptidetrans-
the other cytokines whose receptors share the (cid:13)c
porters,andBcellAPCfunctionisenhancedbyIL-4.
chain(IL-4,IL-7,IL-9,andIL-15).Invivo,Tcellsdo
On the other hand, IL-10 inhibits APC functions by
not appear to require these cytokines for prolifera-
blocking expression of integrin substrates, costimula-
tion, but instead IL-2 is thought to promote cell
tors, and cytokine production.
death.TGF(cid:12) inhibitsTcellproliferation.FasL,acell
surface molecule (but a member of the TNF family),
inducesTcelldeath,eliminatingunneededTcellsafter
antigenhasbeenclearedandalsoprotectssometissues
ARCHITECTURE OF LYMPHOID
from T cell invasion. Many other cytokines also pro-
ORGANS
mote or inhibit T cell proliferation; for example,
interferons suppress T cell replication whereas TNF
or prolactin enhance it. B lymphocyte proliferation is Several of the cytokines are required to induce
promoted by various cytokines, including IL-2, IL-4, nonlymphoidcellstoshapetheorgansthatinturnare
IL-6,IL-10,IL-13,BLYS,andCD40L(notactuallya requiredtosupportimmuneresponses.LT(cid:11)/(cid:12) directs
secreted cytokine but a T cell membrane protein in developmentoflymphnodesandPeyer’spatchesand
thefamilywiththe TNFcytokines).TGF(cid:12) inhibitsB organization of follicular dendritic cell networks in
cell proliferation. thespleen.TNFisrequiredforgerminalcentersinthe
spleen.
LYMPHOID DIFFERENTIATION
CELL TRAFFICKING
The differentiation of activated CD4(cid:135) T cells to the
TH1 versus TH2 lineages is dependent on cytokines. Theimmunesystemhasmanymobilecellsandpartof
IL-12, produced by macrophages and dendritic cells, themechanismdeterminingtheirdestinationsisbased
induces TH1 differentiation and other cytokines that on chemoattraction by chemokines. For example,
also promote TH1 generation include IFN(cid:13), IFN(cid:11), T cells normally recirculate from bloodto lymphatics
IL-1, and IL-18. Differentiation to the TH2 lineage and back to blood. The accumulation of T cells in
depends on IL-4. Cytotoxic T cell development into certain sites in lymph node is attributed to the
TC1 and TC2 lineages responds to cytokine signals chemokineSLC.IL-16(producedbyCD8(cid:135)Tcells)is
that are similar to those promoting their TH1 and chemotacticforCD4(cid:135)cells.Langerhanscellstakeup
TH2 counterparts and the development of cytotoxic antigens in skin, then migrate to specific sites in
function is promoted by IL-2. lymph nodes (attracted by chemokines) where they
B lymphocytes undergo a switch from producing present antigens to T cells. Dendritic cell APCs also
IgM to producing other isotypes. Different cytokines produce chemokines that attract T cells.
Cytokines and the Immune System 97
CONNECTION BETWEEN functions. For example growth hormone and pro-
lactin, products of the pituitary (as well as other
IMMUNE AND INFLAMMATORY
peripheral sources), promote development of lym-
RESPONSES
phocytes, their antigen-driven proliferation, and their
survival. The reverse relationship is also clear, in that
A specific immune response in a tissue generally IL-1, IL-6, and a variety of cytokines produced by
triggersalocalinflammatoryresponseandthereverse immune responses induce profound effects on the
also occurs, a local inflammatory response promotes central nervous system, such as the fever response.
a specific immune response in the tissue and in the
draining lymph nodes. Cytokines mediate this inter-
actionbetweentheimmuneandinflammatorysystems. VIRAL IMMUNOMODULATORS
Forexample,IL-1orTNFproducedatasiteoflocal
RELATED TO CYTOKINES
inflammation induce nearby endothelial cells to
expressbindingsitesforbloodlymphocytes,inducing
Poxvirusesproduceanumberofproteinsthatcombat
theirextravasation.Thereverserelationshipoccursin
cytokine pathways involved in host defense.
an organ allograft, in which specific T cells produce
Nonsignaling homologs of TNFR, IL-1R, and of
chemokines recruiting monocytes to the graft. There
bothtypeIandtypeIIinterferonreceptorshavebeen
are many more examples of cytokines linking the
demonstrated.Thechemokinepathwaysareinhibited
specific immune response to inflammatory cells,
both by nonsignalingreceptor homologsand by non-
hematopoiesis, and even the central nervous system.
signaling ligand homologs. Viruses also produce
cytokine homologs that signal through normal cellu-
lar receptors. IL-10 homologs (which are immuno-
CONNECTION BETWEEN THE
suppressive) are found both in poxviruses and also in
IMMUNE AND CENTRAL
Epstein-Barr virus. Other examples of signaling
NERVOUS SYSTEMS ligands are vaccinia growth factor, which uses the
EGF receptor and induces cell proliferation, and
VEGF homologs that induce vascularization.
Peptide hormones produced by the central nervous
system have been shown to promote several immune