Opa⁺and Opa⁻Isolates ofNeisseria meningitidisandNeisseria gonorrhoeaeInduce Sustained Proliferative Responses in Human CD4⁺T Cells

Abstract

T cells may interact with a number of bacterial surface antigens, an encounter which has the potential to downmodulate host immune responses. Neisseria meningitidis, a human colonizer and an agent of septicemia and meningitis, expresses Opa proteins which interact with the CEACAM1 receptor expressed on activated T cells. Since CEACAM1 can act as an inhibitory receptor and T cells in subepithelial tissues may encounter whole bacteria, which often express Opa proteins in vivo, this study assessed primarily if Opa proteins expressed on meningococci affect T-cell functions. In addition, Opa-containing outer membrane vesicles (OMV) have been used as vaccine antigens, and therefore Opa ؉ and Opa ؊ OMV were also studied. While Opa ؉ bacteria adhered to CEACAM-expressing T cells, both the Opa ؉ and Opa ؊ phenotypes induced no to a small transient depression, followed by a prolonged increase in proliferation as well as cytokine production. Such responses were also observed with heat-killed bacteria or OMV. In addition, while anti-CEACAM antibodies alone inhibited proliferation, on coincubation of T cells with bacteria and the antibodies, bacterial effects predominated and were Opa independent. Thus, while Opa proteins of N. meningitidis can bind to T-cell-expressed CEACAM1, this is not sufficient to overcome the T-cell recognition of bacterial factors, which results in a proliferative and cytokine response, an observation consistent with the ability of the host to establish lasting immunity to Opa-expressing meningococci that it frequently encounters. The data also imply that Opa-proficient vaccine preparations may not necessarily inhibit T-cell functions via CEACAM1 binding.

Expression of human CEACAM1 in transgenic mice limits the Opa-specific immune response against meningococcal outer membrane vesicles

“…This inhibitory effect in the form of reduced T cell cytokine production, proliferation or cytotoxic activity, has been observed in vitro when human peripheral-blood-derived mononuclear cells (PBMCs) were stimulated with T cell activators in the presence of CEACAM1-specific antibodies or Opa proteins of N. meningitidis or Neisseria gonorrhoeae [12,13]. By contrast, other experiments including by our own group found no inhibitory effect of the presence of Opa protein on N. meningitidis or N. gonorrhoeae induced CD4+ T cell responses [15]. A few studies using immobilized CEACAM1 on activated T cells even resulted in opposite effects in which T cell proliferation was enhanced [16,24].…”

“…These processes are mediated mainly by interaction with carcinoembryonic antigen-related cellular adhesion molecules (CEACAMs) found in a wide variety of human tissues [7][8][9][10][11]. Binding of Opa proteins to CEACAMs also plays a part in interactions with the immune system [12][13][14][15].…”

Potential of Recombinant Opa Proteins as Vaccine Candidates against Hyperinvasive Meningococci

“…Conversely, others have found that Opa proteins expressed on the surface of gonococci (4) arrest activation and proliferation of CD4 ϩ T cells via a CEACAM1-mediated mechanism (24). Data from studies using meningococcal OMVs have yielded conflicting results (24,54). More data on the interaction between Opa proteins and CD4 ϩ T cells are therefore required.…”

Selection for a CEACAM Receptor-Specific Binding Phenotype during Neisseria gonorrhoeae Infection of the Human Genital Tract

“…In the female genital tract, squamous epithelia express CEACAM5, whereas CEACAM1 is expressed on columnar epithelia of the endocervix and uterus (27), allowing each to be accessible for direct docking by the gonococci. Moreover, CEACAM1 is widely expressed on lymphocytes, and CEACAM1-induced signaling can influence immune cell activation (28)(29)(30)(31)(32)(33)(34)(35), potentially providing a mechanism for immune evasion by N. gonorrhoeae. While no study to date has looked at CEACAM expression within the male urethra, a transgenic mouse line expressing human CEACAMs in a manner that closely reflects the spatiotemporal expression pattern in humans expresses CEACAM5 on the urethral mucosal surface (36).…”