CD27 and CD70 in T cell and B cell activation

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In vitro work has defined the TNF receptor family member CD27 as a T and B cell co-stimulatory molecule. Its activity is governed by the transient availability of its TNF-like ligand CD70 on lymphocytes and dendritic cells. Recent studies, enforcing or abrogating CD27 function by genetic or protein intervention in mouse models have revealed key contributions of the CD27–CD70 system to effector and memory T cell formation, which is probably based on improved cell survival. The stimulatory effects of CD27 on B cell function appear to oppose those of CD70, which also has a signaling role. Targeting CD27–CD70 for therapy is attractive but should take into account the fact that constitutive CD27 stimulation culminates in lethal immunodeficiency.

Introduction

In peripheral lymphoid organs of naïve mice, CD27 is found on a large proportion of NK cells and on most, if not all, CD4+ and CD8+ T cells [1, 2]. CD27 is absent from naïve B cells, but is induced upon priming [3]. The contribution of CD27 to the immune response is dependent upon CD70 expression, which is primarily controlled by antigen receptor and Toll-like receptor stimulation on T cells, B cells and dendritic cells (DCs) [4]. NK cells can also express CD70 [5]. The expression patterns of CD27 and CD70 in humans are very similar to those in mice, except that CD27 is expressed on primed B cells in higher frequency and more persistently in humans. In clinical practice, membrane CD27 and its soluble form are used as lymphocyte subset markers and disease markers in the case of lymphoid malignancies, autoimmunity and transplant rejection [6, 7, 8]. From in vitro studies on human cells, CD27 has long been known as a co-stimulator of T cell and B cell responses [6, 8, 9]; however, its exact mechanism of action and relative importance for immune responsiveness in vivo are only now being revealed by studies in mouse models. This recent work will be subject of this review.

Section snippets

T cell priming and effector phases

According to their expression patterns, CD27–CD70 interactions can come into play in the T cell priming phase during contact between T cells and DCs and in the expansion phase during contact between T cells. During the effector phase, interactions between CD27 on T cells and CD70 on DCs and B cells may be important, as CD70 is most abundant on these cell types at the effector site (J Hendricks et al., unpublished; Figure 1).

CD27−/− mice, intranasally infected with influenza virus, revealed that

T cell memory

Upon infection with influenza virus [10, 11••], lymphocytic choriomeningitis virus (M Matter and A Ochsenbein, personal communication), or challenge with immunogenic tumor cells (Y Xiao, J Borst, unpublished), secondary CD8+ T cell responses are reduced in CD27−/− mice. Also, CD70 blockade reduced secondary CD8+ T cell responses to cardiac allografts [12], or peptide plus CD40 antibody [20]. Conversely, deliberate CD27 stimulation by challenge with CD70-expressing tumor cells [18, 19, 22], or

The B cell response

The presence of both CD27 and CD70 on primed T and B cells theoretically enables CD27–CD70 interactions to influence the B cell response in many ways (Figure 3). In vitro studies argue that CD27 on human B cells stimulates immunoglobulin production, which is at least in part due to promotion of plasma cell differentiation [25]. In the mouse, CD27 is acquired by a proportion of B cells at the centroblast stage and progressively lost upon their maturation. It is not a marker for somatically

Signaling and cellular responses

Via a conserved motif of amino acids, PIQEDYR CD27 binds the adaptor proteins Traf-2 and Traf-5 and signals to the NF-κB and c-Jun kinase pathways (Figure 4: [29, 30, 31, 32••]). Traf signaling is connected to cell survival, but may also affect other cellular responses, such as differentiation and migration [33]. Recently, an elegant study showed that CD27 activates both canonical and alternative NF-κB pathways via the NF-κB-inducing kinase (NIK), which is a serine/threonine kinase [32••].

Conclusions

CD27–CD70 interactions govern the establishment of CD4+ and CD8+ effector T cell pools at tissue sites in primary and in particular in secondary responses. For CD8+ T cells, it is clear that CD27–CD70 interactions regulate expansion at the site of priming, maintenance at the effector site, contraction and memory formation, as well as secondary expansion. For CD4+ T cells, this remains to be explored. By controlling CD70 expression, antigen controls CD27 function. A major mechanism underlying

Update

The work referred to in the text as (R Arens and RAW van Lier, personal communication) is now in press [48].

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank all cited investigators for making their unpublished data available to us. We are grateful to R Arens and K Schepers for valuable advise on manuscript and figures and to RAW van Lier and TNM Schumacher for critically reading the manuscript. The cited work from our laboratory was supported by grants from the Dutch Cancer Society and the Netherlands Organization for Scientific Research.

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