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Semaphorins in interactions between T cells and antigen-presenting cells

Nature Reviews Immunology volume 3, pages 159–167 (2003)Cite this article

Key Points

  • Semaphorins were identified originally as repulsive axon-guidance factors during neuronal development. It is becoming increasingly clear that several members of the semaphorin family have roles in the immune system.

  • SEMA4D (CD100), a class IV semaphorin, uses two receptors, plexin-B1 and CD72, the latter of which is a functional lymphocyte receptor. SEMA4D enhances B-cell responses by a unique mechanism — turning off the negative signals of CD72.

  • SEMA4D also has a role in the generation of antigen-specific T cells by enhancing the activation and maturation of professional antigen-presenting cells, such as dendritic cells (DCs).

  • ;Another class IV semaphorin, SEMA4A, which is expressed preferentially by DCs, is involved in T-cell activation.

  • Molecular cloning has shown that the receptor for SEMA4A is TIM2, which is expressed on the surface of activated T cells and belongs to the T-cell, immunoglobulin domain and mucin domain (TIM) protein family.

  • In addition, other semaphorins (such as SEMA3A and SEMA7A) and semaphorin receptors (such as neuropilins) seem to have roles in immune responses.

Abstract

Although semaphorins were identified originally as guidance cues for developing neuronal axons, accumulating evidence indicates that several semaphorins are expressed also in the immune system. SEMA4D (CD100), which is expressed constitutively by T cells, enhances the activation of B cells and dendritic cells (DCs) through its cell-surface receptor, CD72. SEMA4A, which is expressed by DCs, is involved in the activation of T cells through interactions with TIM2. So, these semaphorins seem to function in the reciprocal stimulation of T cells and antigen-presenting cells (APCs). Emerging evidence indicates that additional semaphorins and related molecules are involved in T-cell–APC interactions also.

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Figure 1: SEMA4D uses two receptors.
Figure 2: SEMA4D turns off negative signals of CD72.
Figure 3: Involvement of SEMA4A in T-cell activation through TIM2.
Figure 4: Involvement of semaphorins in various phases of T-cell–APC interactions.

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Acknowledgements

We thank K. Kubota for excellent secretarial assistance. We also thank C. Watanabe and N. Takegahara for excellent design of the original figures. This study was supported by research grants from the Ministry of Education, Culture, Science and Technology of Japan to H.K. and A.K.

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Authors and Affiliations

  1. Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, 565-0871, Osaka, Japan

    Hitoshi Kikutani & Atsushi Kumanogoh

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  1. Hitoshi Kikutani
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  2. Atsushi Kumanogoh
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Correspondence to Hitoshi Kikutani.

Related links

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DATABASES

Entrez

A39R

AHV SEMA

LocusLink

CD72

neuropilin-1

plexin-A1

plexin-B1

plexin-C1

SEMA3A

SEMA4A

SEMA4D

SEMA7A

SHP1

TIM1

TIM3

FURTHER INFORMATION

Osaka University Research Institute for Microbial Diseases

Glossary

IMMUNOLOGICAL SYNAPSE

A structure that is formed at the cell surface between a T cell and an antigen-presenting cell; also known as a supra-molecular activation cluster (SMAC). Important molecules that are involved in T-cell activation — including the T-cell receptor, many signal-transduction molecules and molecular adaptors — accumulate at this site.

BCR SIGNALOSOME

A putative, stable signalling complex, which consists of BTK, BLNK, BCAP, VAV1/2, PLCγ2 and PI3K, that is proposed to regulate the level of intracellular calcium and subsequent downstream events of B-cell receptor (BCR) signalling.

EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS

(EAE). Inflammation of the brain and spinal cord that is induced generally by the administration of myelin basic protein or myelin oligodendrocyte glycoprotein, plus adjuvants, to disease-susceptible strains of mice.

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Kikutani, H., Kumanogoh, A. Semaphorins in interactions between T cells and antigen-presenting cells. Nat Rev Immunol 3, 159–167 (2003). https://doi.org/10.1038/nri1003

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