Both infection and vaccination, alone or in combination, generate antibody and T cell responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the maintenance of such ...responses-and hence protection from disease-requires careful characterization. In a large prospective study of UK healthcare workers (HCWs) (Protective Immunity from T Cells in Healthcare Workers PITCH, within the larger SARS-CoV-2 Immunity and Reinfection Evaluation SIREN study), we previously observed that prior infection strongly affected subsequent cellular and humoral immunity induced after long and short dosing intervals of BNT162b2 (Pfizer/BioNTech) vaccination.
Here, we report longer follow-up of 684 HCWs in this cohort over 6-9 months following two doses of BNT162b2 or AZD1222 (Oxford/AstraZeneca) vaccination and up to 6 months following a subsequent mRNA booster vaccination.
We make three observations: first, the dynamics of humoral and cellular responses differ; binding and neutralizing antibodies declined, whereas T and memory B cell responses were maintained after the second vaccine dose. Second, vaccine boosting restored immunoglobulin (Ig) G levels; broadened neutralizing activity against variants of concern, including Omicron BA.1, BA.2, and BA.5; and boosted T cell responses above the 6-month level after dose 2. Third, prior infection maintained its impact driving larger and broader T cell responses compared with never-infected people, a feature maintained until 6 months after the third dose.
Broadly cross-reactive T cell responses are well maintained over time-especially in those with combined vaccine and infection-induced immunity ("hybrid" immunity)-and may contribute to continued protection against severe disease.
Department for Health and Social Care, Medical Research Council.
: RNA silencing experiments showed that knocking down Gab1 adaptor protein in BL41 human Burkitt lymphoma cells significantly reduced B cell receptor (BCR)–induced Erk phosphorylation, indicating ...that Gab1 plays a pivotal role in regulating Erk activity in B cells.
Inflammatory joint destruction in rheumatoid arthritis (RA) may be triggered by autoantibodies, the production of which is supported by autoreactive T cells. Studies on RA and animal models of the ...disease suggest that T cells recruited in the joints can locally initiate or propagate arthritis. Herein, we investigated the role of joint-homing versus lymphoid organ-homing T cells in the development of proteoglycan-induced arthritis (PGIA), an autoimmune model of RA.
To identify T cells migrating to the joints before and during development of autoimmune arthritis, we transferred fluorescence-labeled T cells, along with antigen-presenting cells, from BALB/c mice with PGIA to naïve syngeneic severe combined immunodeficient (SCID) mice. We then monitored the recruitment of donor T cells in the ankle joints and joint-draining lymph nodes of the recipients using in vivo two-photon microscopy and ex vivo detection methods. To limit T-cell access to the joints, we selectively depleted T cells in the blood circulation by treatment with FTY720, an inhibitor of lymphocyte egress from lymphoid organs. Reduction of T cell presence in both lymphoid organs and blood was achieved by injection of donor cells from which T cells were removed prior to transfer. T and B cells were quantitated by flow cytometry, and antigen (PG)-specific responses were assessed by cell proliferation and serum antibody assays.
Despite development of adoptively transferred arthritis in the recipient SCID mice, we found very few donor T cells in their joints after cell transfer. Treatment of recipient mice with FTY720 left the T-cell pool in the lymphoid organs intact, but reduced T cells in both peripheral blood and joints. However, FTY720 treatment failed to inhibit PGIA development. In contrast, arthritis was not seen in recipient mice after transfer of T cell-depleted cells from arthritic donors, and serum autoantibodies to PG were not detected in this group of mice.
Our results suggest that antigen-specific T cells, which home to lymphoid organs and provide help to B cells for systemic autoantibody production, play a greater role in the development and progression of autoimmune arthritis than the small population of T cells that migrate to the joints.
AbstractRNA silencing experiments showed that knocking down Gab1 adaptor protein in BL41 human Burkitt lymphoma cells significantly reduced B cell receptor (BCR)-induced Erk phosphorylation, ...indicating that Gab1 plays a pivotal role in regulating Erk activity in B cells.
Immune complexes (ICs) induce effective pathogen-specific innate and humoral immune response via immunecomplex-binding receptors, such as murine complement receptor type 1 and 2 (mCR1/2) and murine ...low-affinity Fc receptors for IgG (mFcIsup3RII and III). The exact function of mCR1/2 in cooperation with mFcIsup3RII/III in modulation of humoral immunity has not yet been adequately clarified. The aim of this study was to target these receptors by specific single-chain fragments of antibody (scFv), either individually or in combination, thus modelling the action of IC. For targeting, we used scFv derived from the well-characterized 7g6 and 2.4g2 monoclonal antibodies recognizing mCR1/2 and mFcIsup3RII/III, respectively. These scFvs were monobiotinylated and conjugated to streptavidin or streptavidin-coated microspheres. Such complexes were investigated with respect to target receptor recognition and in vivo localization. Antibody response against the constructs was measured by ELISA and ELISPOT. Results show that targeting streptavidin complexes to mFcIsup3RII/III induces stronger IgG1 response than targeting to mCR1/2 yet both strategies enhance the antibody response compared to the control group immunized with non-targeted peptide-streptavidin complexes. Moreover, the immunogenicity of coupled antigens increased using microspheres as carrier, instead of using soluble streptavidin. In summery, our in vivo experiments reveal that mFcIsup3RII/III is more potent a target than CR1/2 and show that combined targeting of CR1/2 and FcIsup3RII/III receptors does not result in cumulative enhancement of the antigen specific immune response. In addition, microparticle-mediated enhancement of immunization can be further improved by FcIsup3RII/III targeting.
Abstract Immune complexes (ICs) induce effective pathogen-specific innate and humoral immune response via immunecomplex-binding receptors, such as murine complement receptor type 1 and 2 (mCR1/2) and ...murine low-affinity Fc receptors for IgG (mFcγRII and III). The exact function of mCR1/2 in cooperation with mFcγRII/III in modulation of humoral immunity has not yet been adequately clarified. The aim of this study was to target these receptors by specific single-chain fragments of antibody (scFv), either individually or in combination, thus modelling the action of IC. For targeting, we used scFv derived from the well-characterized 7g6 and 2.4g2 monoclonal antibodies recognizing mCR1/2 and mFcγRII/III, respectively. These scFvs were monobiotinylated and conjugated to streptavidin or streptavidin-coated microspheres. Such complexes were investigated with respect to target receptor recognition and in vivo localization. Antibody response against the constructs was measured by ELISA and ELISPOT. Results show that targeting streptavidin complexes to mFcγRII/III induces stronger IgG1 response than targeting to mCR1/2 yet both strategies enhance the antibody response compared to the control group immunized with non-targeted peptide–streptavidin complexes. Moreover, the immunogenicity of coupled antigens increased using microspheres as carrier, instead of using soluble streptavidin. In summery, our in vivo experiments reveal that mFcγRII/III is more potent a target than CR1/2 and show that combined targeting of CR1/2 and FcγRII/III receptors does not result in cumulative enhancement of the antigen specific immune response. In addition, microparticle-mediated enhancement of immunization can be further improved by FcγRII/III targeting.
B cells participate in the induction and maintenance of systemic autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, via production of pathogenic autoantibodies, ...contributing to the formation of immune complexes. Immune complex deposition in the kidney and joints causes inflammation and organ destruction, and chemokine production enhances T cell activation and tissue damage. The development of the disorder depends on several factors, for example, genetic susceptibility, environmental factors or immune dysregulation. Traditional therapies, which aimed at the alleviation of symptoms, are giving way to biological therapies with the potential of disrupting disease progression. This article focuses on antibody therapies, especially on the applications of single-chain antibodies, as new biological agents for the treatment of systemic autoimmune disorders.
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