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: 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 the immune system. The immune processes controlled by cytokines will be introduced in this overview, which covers molecules termed `immunomodulatory cytokines' in this database as well as other cytokines and peptide hormones. The immune response is modulated 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 direct effects of cytokines on mature cells of the immune system, the development of immune cells depends on cytokines (IL-7, SCF, Flt-3L, SDF, IL-15) as does the architecture of lymphoid organs (LT, TNF). Cytokines link the immune system with the inflammatory response (IL-1, IL-6, TNF) and with the central nervous system (growth hormone, prolactin, IL-1). Viruses produce a number of agents that combat cytokine pathways (IFN, TNF, IL-1, chemokines) or suppress (IL-10) processes involved in antiviral immunity.

BACKGROUND
The immune response to foreign antigens is based on the remarkable activities of a rather small number of lymphocytes that specifically recognize each antigen. The immune response culminates in the elimination of these antigens using an armamentarium of immunoglobulins, cytolytic T cells, and recruited inflammatory cells that engulf the invaders.

An early controversy among immunologists in the 1970s concerned the mechanism by which T cells helped B cells to produce antibody, some immunologists favoring cytokines, others favoring cell contact. Now that a number of the mechanisms are understood at the molecular level, the distinction between cell-bound and secreted molecules has become somewhat blurred. Many of the integral membrane molecules (like CD40L) are actually very similar to released molecules (like TNF). Moreover, many of the secreted cytokines (like chemokines, TGF, and IL-7) are probably not actually recognized in their soluble forms, but rather in a form attached to other membranes and extracellular matrix. Early immunological studies identified soluble activities made by lymphocytes or acting upon lymphocytes (the earlier term `lymphokine' has been supplanted by the broader term `cytokine'). The activities included proliferation of T cells, B cells, and thymocytes, induction of Ig secretion, cytotoxic T cell generation, cell death, macrophage activation, and a host of other immune and inflammatory responses. The ability to clone cytokines has greatly moved research, and the production of knockout mice has placed each cytokine in a physiological perspective. This chapter will outline the general types of immunological processes regulated by the cytokines, referring the reader to individual chapters for in-depth treatments and bibliographies.

LYMPHOID DEVELOPMENT
T cell development in the thymus requires several cytokines. IL-7 is required for pro-T cells to survive

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Scott K. Durum induce the switch to different isotypes. IL-4 or IL-13 induce switch to IgE and IgG1, IFN induces switch to IgG2a and IgG3, and TGF induces switching to IgA. All switching requires CD40L. IL-2, IL-10, and IL-15 also promote Ig production, whereas TGF inhibits Ig secretion. Memory B cell development is induced by CD40L.

and rearrange the genes encoding some of the antigen receptors. TSLP, an IL-7 homolog, also has activities. SCF and Flt-3 ligand are involved in proliferation and survival of early thymocyte stages. Negative selection of intermediate thymocyte stages is partly mediated by FasL and CD30L. B cell development in bone marrow depends on the chemokine SDF. In mice (but not humans) B cell development also depends on IL-7. TSLP appears to promote early B cell developmental stages. Large granular lymphocytes (NK cells) require IL-15 for development. In all these cases, other stromal cell surface molecules, in addition to the secreted cytokines, are required.

ANTIGEN-PRESENTING CELLS
The activation of T cells is dependent on antigenpresenting cells (APCs) which in turn depend on cytokines to induce their differentiation from precursors to become active APCs. The development and APC function of dendritic cells has been induced by various cocktails of cytokines that have incorporated GM-CSF, TNF, TGF, CD40L, IL-1, and IL-4. Macrophage APC function is enhanced by IFN which increases the levels of MHC and peptide transporters, and B cell APC function is enhanced by IL-4. On the other hand, IL-10 inhibits APC functions by blocking expression of integrin substrates, costimulators, and cytokine production.

LYMPHOID PROLIFERATION AND SURVIVAL

Activated T cells proliferate in response to IL-2 or to the other cytokines whose receptors share the c chain (IL-4, IL-7, IL-9, and IL-15). In vivo, T cells do not appear to require these cytokines for proliferation, but instead IL-2 is thought to promote cell death. TGF inhibits T cell proliferation. FasL, a cell surface molecule (but a member of the TNF family), induces T cell death, eliminating unneeded T cells after antigen has been cleared and also protects some tissues from T cell invasion. Many other cytokines also promote or inhibit T cell proliferation; for example, interferons suppress T cell replication whereas TNF or 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 a secreted cytokine but a T cell membrane protein in the family with the TNF cytokines). TGF inhibits B cell proliferation.

ARCHITECTURE OF LYMPHOID ORGANS

Several of the cytokines are required to induce nonlymphoid cells to shape the organs that in turn are required to support immune responses. LT/ directs development of lymph nodes and Peyer's patches and organization of follicular dendritic cell networks in the spleen. TNF is required for germinal centers in the spleen.

LYMPHOID DIFFERENTIATION
The differentiation of activated CD4 T cells to the TH1 versus TH2 lineages is dependent on cytokines. IL-12, produced by macrophages and dendritic cells, induces TH1 differentiation and other cytokines that also promote TH1 generation include IFN, IFN, IL-1, and IL-18. Differentiation to the TH2 lineage depends on IL-4. Cytotoxic T cell development into TC1 and TC2 lineages responds to cytokine signals that are similar to those promoting their TH1 and TH2 counterparts and the development of cytotoxic function is promoted by IL-2. B lymphocytes undergo a switch from producing IgM to producing other isotypes. Different cytokines

CELL TRAFFICKING
The immune system has many mobile cells and part of the mechanism determining their destinations is based on chemoattraction by chemokines. For example, T cells normally recirculate from blood to lymphatics and back to blood. The accumulation of T cells in certain sites in lymph node is attributed to the chemokine SLC. IL-16 (produced by CD8 T cells) is chemotactic for CD4 cells. Langerhans cells take up antigens in skin, then migrate to specific sites in lymph nodes (attracted by chemokines) where they present antigens to T cells. Dendritic cell APCs also produce 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 reverse also occurs, a local inflammatory response promotes a specific immune response in the tissue and in the draining lymph nodes. Cytokines mediate this interaction between the immune and inflammatory systems. For example, IL-1 or TNF produced at a site of local inflammation induce nearby endothelial cells to express binding sites for blood lymphocytes, inducing their extravasation. The reverse relationship occurs in an organ allograft, in which specific T cells produce chemokines recruiting monocytes to the graft. There are many more examples of cytokines linking the specific immune response to inflammatory cells, hematopoiesis, and even the central nervous system.

functions. For example growth hormone and prolactin, products of the pituitary (as well as other peripheral sources), promote development of lymphocytes, their antigen-driven proliferation, and their survival. The reverse relationship is also clear, in that IL-1, IL-6, and a variety of cytokines produced by immune responses induce profound effects on the central nervous system, such as the fever response.

VIRAL IMMUNOMODULATORS RELATED TO CYTOKINES

Poxviruses produce a number of proteins that combat cytokine pathways involved in host defense. Nonsignaling homologs of TNFR, IL-1R, and of both type I and type II interferon receptors have been demonstrated. The chemokine pathways are inhibited both by nonsignaling receptor homologs and by nonsignaling ligand homologs. Viruses also produce cytokine homologs that signal through normal cellular receptors. IL-10 homologs (which are immunosuppressive) are found both in poxviruses and also in Epstein-Barr virus. Other examples of signaling ligands are vaccinia growth factor, which uses the EGF receptor and induces cell proliferation, and VEGF homologs that induce vascularization.

CONNECTION BETWEEN THE IMMUNE AND CENTRAL NERVOUS SYSTEMS

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