The complement system is a powerful innate mechanism involved in protection of the host against pathogens. It also has a role in the clearance of apoptotic cells and has been implicated in a range of pathologies including autoimmunity and graft rejection. The control of complement is mediated through the complement regulatory proteins (CRPs). These are present on most cells and protect normal cells from complement-mediated attack during innate activation. However, in a range of pathologies and cancer, these molecules are up or down regulated, sometimes secreted and even lost. We will review the expression of CRPs in cancer, focussing on CD55 and highlight other roles of the CRPs and their involvement in leukocyte function. We will also provide some data providing a potential mechanism by which soluble CD55 can inhibit T-cell function and discuss some of the implications of this data.

Purpose: CD55 is a complement regulatory protein expressed by cells to protect them from bystander attack by complement. CD55 is overexpressed on some tumor cell lines, and in colorectal carcinomas, it has been shown to be an indicator of poor prognostic.Experimental Design: A large set of samples (480) from patients with primary operable breast cancer followed for 4 -192 months were included in the present study. The prognostic significance of CD55 was then investigated in these tumors using an anti-CD55 monoclonal antibody (RM1) that we raised against a synthetic peptide and a standard immunohistochemistry method.Results: Ninety-five percent of the breast carcinomas expressed CD55 (RM1) with intensity ranging from weak (51%) to strong (6%). High expression of CD55 was significantly associated with low-grade (grades 1 or 2; P ‫؍‬ 0.001), lymph node negativity (P ‫؍‬ 0.031), and good prognosis tumors (Nottingham Prognostic Index < 3.4; P < 0.001). Survival analysis showed CD55 overexpression was associated with a more favorable outcome and loss of CD55 being associated with poor survival (P ‫؍‬ 0.001). Intensity of CD55 expression was significantly correlated (P ‫؍‬ 0.002) with intensity of CD59 expression (as shown in a previous study) in these series of patients.Conclusions: In conclusion, we found that loss of both CD55 and CD59 in breast carcinomas is associated with a worse prognosis.

Unlike other helper T cells, the costimulatory ligands responsible for T regulatory type 1 (Tr1) cell differentiation remain undefined. Understanding the molecular interactions driving peripheral Tr1 differentiation is important because Tr1s potently regulate immune responses by IL-10 production. In this study, we show that costimulation of human naive CD4+ cells through CD97/CD55 interaction drives Tr1 activation, expansion, and function. T cell activation and expansion was equipotent with CD55 or CD28 costimulation; however, CD55 costimulation resulted in two IL-10–secreting populations. Most IL-10 was secreted by the minor Tr1 population (IL-10highIFN-γ−IL-4-, &lt;5% cells) that expresses Tr1 markers CD49b, LAG-3, and CD226. This Tr1 phenotype was not restimulated by CD28. However, on CD55 restimulation, Tr1s proliferated and maintained their differentiated IL-10high phenotype. The Tr1s significantly suppressed effector T cell function in an IL-10–dependent manner. The remaining (&gt;95%) cells adopted a Th1-like IFN-γ+ phenotype. However, in contrast to CD28-derived Th1s, CD55-derived Th1s demonstrated increased plasticity with the ability to coexpress IL-10 when restimulated through CD55 or CD28. These data identify CD55 as a novel costimulator of human Tr1s and support a role for alternative costimulatory pathways in determining the fate of the growing number of T helper populations. This study demonstrates that CD55 acts as a potent costimulator and activator of human naive CD4+ cells, resulting in the differentiation of a discrete Tr1 population that inhibits T cell function in an IL-10–dependent manner and maintains the Tr1 phenotype upon restimulation.

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