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Cytokines and the

Immune SystemScott K. Durum*

Laboratory of Molecular Immunoregulation, National Cancer Institute, FCRDC, DBS Building,Room 31-73, Frederick, MD 21702-1201, USA

* corresponding author tel: 301-846-1545, fax: 301-846-6720, e-mail: durums@mail.ncifcrf.gov

DOI: 10.1006/rwcy.2000.02001.

SUMMARY

Cytokines are important signaling molecules in theimmune system. The immune processes controlled bycytokines will be introduced in this overview, whichcovers molecules termed `immunomodulatory cyto-kines' in this database as well as other cytokines andpeptide hormones. The immune response is modu-lated by cytokines that affect cell proliferation (IL-2,IL-4, growth hormone, TGF, and many others),survival (IL-7, prolactin, FasL), differentiation (IL-4,IL-12), antigen presentation (GM-CSF, IFN, IL-10)and trafficking (chemokines). In addition to the directeffects of cytokines on mature cells of the immunesystem, the development of immune cells depends oncytokines (IL-7, SCF, Flt-3L, SDF, IL-15) as does thearchitecture of lymphoid organs (LT,TNF). Cytokineslink the immune system with the inflammatory res-ponse (IL-1, IL-6, TNF) and with the central nervoussystem (growth hormone, prolactin, IL-1). Virusesproduce a number of agents that combat cytokinepathways (IFN, TNF, IL-1, chemokines) or suppress(IL-10) processes involved in antiviral immunity.

BACKGROUND

The immune response to foreign antigens is based onthe remarkable activities of a rather small number oflymphocytes that specifically recognize each antigen.The immune response culminates in the elimination ofthese antigens using an armamentarium of immuno-globulins, cytolytic T cells, and recruited inflamma-tory cells that engulf the invaders.

An early controversy among immunologists in the1970s concerned the mechanism by which T cellshelped B cells to produce antibody, some immunol-ogists favoring cytokines, others favoring cell contact.Now that a number of the mechanisms are under-stood at the molecular level, the distinction betweencell-bound and secreted molecules has become some-what blurred. Many of the integral membranemolecules (like CD40L) are actually very similar toreleased molecules (like TNF). Moreover, many ofthe secreted cytokines (like chemokines, TGF, andIL-7) are probably not actually recognized in their

soluble forms, but rather in a form attached to othermembranes and extracellular matrix.

Early immunological studies identified solubleactivities made by lymphocytes or acting uponlymphocytes (the earlier term `lymphokine' has beensupplanted by the broader term `cytokine'). Theactivities included proliferation of T cells, B cells, andthymocytes, induction of Ig secretion, cytotoxic T cellgeneration, cell death, macrophage activation, and ahost of other immune and inflammatory responses.The ability to clone cytokines has greatly movedresearch, and the production of knockout mice hasplaced each cytokine in a physiological perspective.This chapter will outline the general types of immu-nological processes regulated by the cytokines, refer-ring the reader to individual chapters for in-depthtreatments and bibliographies.

LYMPHOID DEVELOPMENT

T cell development in the thymus requires severalcytokines. IL-7 is required for pro-T cells to survive

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and rearrange the genes encoding some of the antigenreceptors. TSLP, an IL-7 homolog, also has activities.SCF and Flt-3 ligand are involved in proliferationand survival of early thymocyte stages. Negativeselection of intermediate thymocyte stages is partlymediated by FasL and CD30L. B cell development inbone marrow depends on the chemokine SDF. In mice(but not humans) B cell development also depends onIL-7. TSLP appears to promote early B cell dev-elopmental stages. Large granular lymphocytes (NKcells) require IL-15 for development. In all thesecases, other stromal cell surface molecules, in additionto the secreted cytokines, are required.

LYMPHOID PROLIFERATION

AND SURVIVAL

Activated T cells proliferate in response to IL-2 or tothe other cytokines whose receptors share the cchain (IL-4, IL-7, IL-9, and IL-15). In vivo, T cells donot appear to require these cytokines for prolifera-tion, but instead IL-2 is thought to promote celldeath. TGF inhibits T cell proliferation. FasL, a cellsurface molecule (but a member of the TNF family),induces T cell death, eliminating unneeded T cells afterantigen has been cleared and also protects some tissuesfrom T cell invasion. Many other cytokines also pro-mote or inhibit T cell proliferation; for example,interferons suppress T cell replication whereas TNFor prolactin enhance it. B lymphocyte proliferation is

promoted by various cytokines, including IL-2, IL-4,IL-6, IL-10, IL-13, BLYS, and CD40L (not actually asecreted cytokine but a T cell membrane protein inthe family with the TNF cytokines). TGF inhibits Bcell proliferation.

LYMPHOID DIFFERENTIATION

The differentiation of activated CD4 T cells to theTH1 versus TH2 lineages is dependent on cytokines.IL-12, produced by macrophages and dendritic cells,

induces TH1 differentiation and other cytokines thatalso promote TH1 generation include IFN, IFN,IL-1, and IL-18. Differentiation to the TH2 lineagedepends on IL-4. Cytotoxic T cell development intoTC1 and TC2 lineages responds to cytokine signalsthat are similar to those promoting their TH1 andTH2 counterparts and the development of cytotoxicfunction is promoted by IL-2.

B lymphocytes undergo a switch from producingIgM to producing other isotypes. Different cytokines

induce the switch to different isotypes. IL-4 or IL-13induce switch to IgE and IgG1, IFN induces switchto IgG2a and IgG3, and TGF induces switching toIgA. All switching requires CD40L. IL-2, IL-10, andIL-15 also promote Ig production, whereas TGFinhibits Ig secretion. Memory B cell development is

induced by CD40L.

ANTIGEN-PRESENTING CELLS

The activation of T cells is dependent on antigen-presenting cells (APCs) which in turn depend oncytokines to induce their differentiation from pre-cursors to become active APCs. The development andAPC function of dendritic cells has been induced byvarious cocktails of cytokines that have incorporatedGM-CSF, TNF, TGF, CD40L, IL-1, and IL-4.

Macrophage APC function is enhanced by IFNwhich increases the levels of MHC and peptide trans-porters, and B cell APC function is enhanced by IL-4.On the other hand, IL-10 inhibits APC functions byblocking expression of integrin substrates, costimula-tors, and cytokine production.

ARCHITECTURE OF LYMPHOID

ORGANS

Several of the cytokines are required to induce

nonlymphoid cells to shape the organs that in turn arerequired to support immune responses. LT/directsdevelopment of lymph nodes and Peyer's patches andorganization of follicular dendritic cell networks inthe spleen. TNF is required for germinal centers in thespleen.

CELL TRAFFICKING

The immune system has many mobile cells and part ofthe mechanism determining their destinations is based

on chemoattraction by chemokines. For example,T cells normally recirculate from blood to lymphaticsand back to blood. The accumulation of T cells incertain sites in lymph node is attributed to thechemokine SLC. IL-16 (produced by CD8 T cells) ischemotactic for CD4 cells. Langerhans cells take upantigens in skin, then migrate to specific sites inlymph nodes (attracted by chemokines) where theypresent antigens to T cells. Dendritic cell APCs alsoproduce chemokines that attract T cells.

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CONNECTION BETWEEN

IMMUNE AND INFLAMMATORY

RESPONSES

A specific immune response in a tissue generally

triggers a local inflammatory response and the reversealso occurs, a local inflammatory response promotesa specific immune response in the tissue and in thedraining lymph nodes. Cytokines mediate this inter-action between the immune and inflammatory systems.For example, IL-1 or TNF produced at a site of localinflammation induce nearby endothelial cells toexpress binding sites for blood lymphocytes, inducingtheir extravasation. The reverse relationship occurs inan organ allograft, in which specific T cells producechemokines recruiting monocytes to the graft. Thereare many more examples of cytokines linking thespecific immune response to inflammatory cells,

hematopoiesis, and even the central nervous system.

CONNECTION BETWEEN THE

IMMUNE AND CENTRAL

NERVOUS SYSTEMS

Peptide hormones produced by the central nervoussystem have been shown to promote several immune

functions. For example growth hormone and pro-lactin, products of the pituitary (as well as otherperipheral sources), promote development of lym-phocytes, their antigen-driven proliferation, and theirsurvival. The reverse relationship is also clear, in thatIL-1, IL-6, and a variety of cytokines produced byimmune responses induce profound effects on thecentral nervous system, such as the fever response.

VIRAL IMMUNOMODULATORS

RELATED TO CYTOKINES

Poxviruses produce a number of proteins that combatcytokine pathways involved in host defense.Nonsignaling homologs of TNFR, IL-1R, and ofboth type I and type II interferon receptors have beendemonstrated. The chemokine pathways are inhibitedboth by nonsignaling receptor homologs and by non-signaling ligand homologs. Viruses also producecytokine homologs that signal through normal cellu-lar receptors. IL-10 homologs (which are immuno-suppressive) are found both in poxviruses and also inEpstein-Barr virus. Other examples of signalingligands are vaccinia growth factor, which uses theEGF receptor and induces cell proliferation, andVEGF homologs that induce vascularization.

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