Waning and aging of cellular immunity to Bordetella pertussis

Abstract

While it is clear that the maintenance of Bordetella pertussis-specific immunity evoked both after vaccination and infection is insufficient, it is unknown at which pace waning occurs and which threshold levels of sustained functional memory B and T cells are required to provide long-term protection. Longevity of human cellular immunity to B. pertussis has been studied less extensively than serology, but is suggested to be key for the observed differences between the duration of protection induced by acellular vaccination and whole cell vaccination or infection. The induction and maintenance of levels of protective memory B and T cells may alter with age, associated with changes of the immune system throughout life and with accumulating exposures to circulating B. pertussis or vaccine doses. This is relevant since pertussis affects all age groups. This review summarizes current knowledge on the waning patterns of human cellular immune responses to B. pertussis as addressed in diverse vaccination and infection settings and in various age groups. Knowledge on the effectiveness and flaws in human B. pertussis-specific cellular immunity ultimately will advance the improvement of pertussis vaccination strategies.

Keywords: B cells; Bordetella pertussis; T cells; aging; infection; vaccination.

Graphical Abstract Figure.

Waning and aging features of human B- and T-cell responses specific for Bordetella pertussis are discussed, and this knowledge may be instrumental in the development of improved vaccines and vaccination strategies for pertussis.

Figure 1.

Multiple cognate interactions between B cells and CD4⁺ T cells specifc for B. pertussis. (A) Development of primary and recall B- and T-cell responses: The presence of B. pertussis (or antigens) trapped in draining lymph nodes is sensed by naïve B cells with IgM B cell receptors (BCR) with low affinity for antigen. Naïve B cells become activated, take up antigen via their BCR into lysosomal compartments, and process and present antigenic peptides in the context of MHC class II molecules. Dendritic cells (DC) also sense the pathogen, become activated and start presenting antigenic peptides in the context of MHC class II molecules while migrating to the draining lymph node, where they activate naïve CD4⁺ T cells with T-cell receptors (TCR) specific for the presented MHC class II-peptide complexes. CD4⁺ T-cell proliferate and differentiate into different functional subsets (Th1, Th2, Th17, Treg, T_FH). Surface expression of CXCR5 enables activated B and T_FH cells to comigrate to the CXCL13 rich B–T cell borders of the draining lymph node. Visualized are four stages (1–4) in the development of adaptive immune response in lymphoid organs in which reciprocal interactions between activated B cells and CD4⁺ T_FH cells with the same antigen specificity determine the clonal burst, differentiation and maintenance of both memory B and CD4⁺ T cell subsets (based on current literature and adapted from Tangye and Tarlinton ; Yoshida et al. ; Crotty ; McHeyzer-Williams et al. 2012). Stage 1: B cells that have productive and long-lasting interaction with specific CD4⁺ T_FH cells are licensed to start a germinal center (GC) reaction in which B cells undergo activation-induced cytidine deaminase (AID)-mediated BCR class switching and affinity maturation through somatic hypermutation. Activated B cells lacking cognate CD4⁺ T cell help can clonally expand and proceed into non-GC short-lived plasma cell development that may involve class switching to IgG. Inset: molecular interactions between activated B and T_FH cells in stage 1 are detailed in Fig. 1B and are representative for interactions at subsequent stages. Stage 2: GC B cells with sufficiently adapted BCR receive survival signals from CD4⁺ T_FH cells and leave the GC as either long-lived plasma cells or memory B cells. Stage 3: low amounts of recall antigen are sensed by memory B cells, taken up and processed and presented to memory CD4⁺ T_FH cells that localize close to B-cell follicles. In the secondary response, memory B cells are the prime antigen presenting cells for CD4⁺ T cells, which localize close to the B-cell follicles. Productive interaction with memory T_FH cells promotes memory B-cell expansion and 2nd plasma cell generation. Also a 2nd GC reaction can be started. Stage 4: 2nd GC B cells with further refined BCRs receive survival signals from 2nd CD4⁺ T_FH cells and can leave the GC. Whether 2^nd GC reactions generate both long-lived plasma cells and memory B cells like primary GC reactions is ill defined. IgM, IgG, IgA, IgE: Immunoglobulin M, -G, -A, -E. (B) [Inset:] Receptors and signals involved in cognate interaction between activated B and CD4⁺ T_FH cells sharing specificity for a B. pertussis antigen (also representative for other functional subsets of specific CD4⁺ T cells). Cognate interaction is promoted through CXCR5-mediated colocalization in the lymph node based on chemokine attraction. Reciprocal licensing occurs through MHC class II restricted recognition of CD4⁺ T_FH cells of cognate B. pertussis-specific peptides processed and presented by B. pertussis-specific B cells that have taken up antigen via their BCR. Efficiency of MHC class II presentation of peptide fragments is enhanced by BCR affinity for antigen. Further modifying interactions between specific B cells and CD4⁺ T_FH cells occur via accessory molecules, such as CD40-CD40L, OX40L-OX40, ICOS-ICOSL and (not shown) SLAM. Cells also exchange differentiation, proliferation and survival signals via cytokine production and expression of cytokine receptors. Recently, it was found that CD4⁺ T_FH cells besides predominantly expressing IL-21 can also secrete IL-4 and IFN-γ, known to regulate B-cell responses (Reinhardt, Liang and Locksley 2009).

Figure 1.

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Figure 2.

Early and steady-state Ptx-specific B- and T-cell responses in (ex-) pertussis cases and impact of age. B cell (A) and T cell (B) responsiveness to Ptx in symptomatic (ex-) pertussis cases are two dimensionally plotted in relation to time elapsed after last exposure to antigen or diagnosis (Y-axes) and age at blood donation (X-axes). Responses are subgrouped in recently exposed (<3 months after date of diagnosis or after date of last vaccination if vaccination took place after clinical infection) versus retrospectively exposed (≥3 months) cases (Y-axis) and in younger (<35 years) versus older (≥35 years) age at blood sampling. Peripheral blood was obtained after informed consent from (ex-)pertussis cases at various time points after their laboratory confirmed diagnosis of symptomatic B. pertussis infection as part of the observational SKI-study (NVI-243, ABR NL16334.040.070). (A) Thawed PBMC from 179 (ex-)pertussis cases were cultured for 5 days in culture medium supplemented with an optimized cocktail of polyclonal and specific stimuli (3 mg/ml CpG, 10 ng/ml IL-10 and 10 ng/ml Ptx) to differentiate B_mem cells into ASC. Ptx-specific ASC were determined by using an ELISpot assay. Spots from at least two countable cell dilutions were used and expressed as geometric mean ASC per 10⁵ plated cells. Negative control wells not coated with Ptx but incubated with cells were used to calculate background. These background spot numbers were subtracted from the antigen-specific ASC. In 32 of tested pertussis cases (18%), B. pertussis infection was not the last exposure to Ptx, due to later vaccination. Strength of Ptx-specific B_mem cell responses was classified and indicated per case (white = no response ACS/10⁵ PBMC <2, green = medium response ACS/10⁵ PBMC 2–70, and red = strong response ACS/10⁵ PBMC > 70). The percentages in the quadrants indicate the fraction of strong Ptx-specific ACS responses of the studied subgroup. Waning of strong B_mem cell responsiveness in time was seen across age groups, being highest in older cases. In the early phase after exposure, strong responses were seen more frequently in younger versus older cases (Fisher's exact test, P = 0.0121). (B) Fresh PBMC from 62 (ex-) pertussis cases were stimulated with 1 μg/ml heat-inactivated Ptx protein for 7 days and Ptx-specific proliferation was assed using [³H]Thymidine incorporation the last 18 hours. Stimulation Index (S.I. = geomean CPM peptide/geomean CPM medium) was calculated. Strength of Ptx-specific T-cell responsiveness was classified and indicated per case (white = no response S.I. < 2, green = medium response S.I. 2–10, and red = strong response S.I. > 10). The percentages in the quadrants indicate the fraction of cases with strong Ptx lymphoproliferative responses of the studied subgroup. Waning of strong Ptx-specific lymphoproliferation in time was seen across age groups, but was highest in the older cases (Fisher's exact test, P = 0.0391).