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. 2004 Jan;111(1):1–7. doi: 10.1111/j.1365-2567.2003.01775.x

T lymphocyte dependence of the antibody response to ‘T lymphocyte independent type 2’ antigens

A Jeurissen *, J L Ceuppens †, X Bossuyt *
PMCID: PMC1782396  PMID: 14678191

Introduction

With regard to their capacity for antibody induction, antigens can be classified as either T lymphocyte dependent (TD) or as T lymphocyte independent (TI).1 In the immune response to TD antigens, T lymphocyte help to B lymphocytes is essential for the regulation of B lymphocyte proliferation, production of immunoglobulins, immunoglobulin class switching, rescue of B lymphocytes from apoptotic death, germinal centre formation, and generation of B lymphocyte memory.2 In contrast to TD antigens, TI antigens induce antibody production without the help of T lymphocytes. TI antigens can be further divided into TI type 1 antigens (TI-1), which are polyclonal B lymphocyte activators (e.g. lipopolysaccharides), and TI type 2 (TI-2) antigens. TI-2 antigens are able to directly stimulate B lymphocytes. However, the antibody response to TI-2 antigens is somehow influenced by T lymphocytes.3 TI-2 antigens do not induce immunological memory and antibodies to TI-2 antigens in humans only develop after the age of 2 years.4,5

Generally, TI-2 antigens are antigens that consist of repetitive biochemical structures such as polymeric protein antigens, trinitrophenyl-ficoll (TNP-ficoll), and dinitrophenyl-ficoll (DNP-ficoll). A clinically important group among the TI-2 antigens are the bacterial capsular polysaccharides.6 Capsular polysaccharides of Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis are responsible for the bacterial virulence and antibodies to capsular polysaccharides provide protection against invasive infections with these bacteria.7 The delay in antibody formation to encapsulated bacteria renders infants and young children highly susceptible to infections with encapsulated bacteria, especially from the ages of 4 to 6 months on, when the placentally derived maternal IgG is metabolized.5 Therefore, children younger than 2 years of age are more at risk for invasive infections caused by encapsulated micro-organisms.8 Children with a persisting defect in the production of antibodies specific for pneumococcal capsular antigens after this age have the so-called ‘specific antibody deficiency with normal immunoglobulins’ (SADNI). They suffer from recurrent pneumococcal infections, although their immunoglobulin and immunoglobulin subclass levels and responses to protein antigens are normal.9–12 It is estimated that 5–10% of the children referred for evaluation of recurrent infections have SADNI and it is therefore highly important to understand the immunological background of the antibody formation against TI-2 antigens.13 In this review we will summarize the current understanding of how T lymphocytes modulate the antibody response against TI-2 antigens.

Second signal hypothesis and role of t lymphocytes

The ‘two signal hypothesis’ for the generation of antibodies to TI-2 has been proposed by Vos et al.14,15 The first signal is the membrane immunoglobulin cross-linking by multivalent TI-2 antigens (Fig. 1). Structural analysis of TI-2 antigens showed that they all have a minimal molecular weight of 100 000 MW and repetitive epitopes that are expressed with a two-dimensional spacing.16 In the immune response to TI-2 antigens, cross-linking of clusters of membrane immunoglobulin molecules is critical for B-lymphocyte stimulation. It was estimated that B-lymphocyte activation requires cross-linking of a minimum of 10–20 membrane immunoglobulin receptors.17

Figure 1.

Figure 1

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Activation of B lymphocyte by TI-2 antigens (e.g. caps-PS). In a first step, caps-PS cross-link multiple membrane bound immunoglobulins (mIg). Subsequently, complement component split product C3d, which is bound to caps-PS, binds to CD21 (complement receptor 2, CR2). This results in B lymphocyte activation and anticaps-PS antibody production.

The second signal is provided through non-antigen-specific stimuli and receptors. Two categories can be distinguished: those which directly target the B lymphocytes and those which have indirect effects, via induction of cytokines or via expression of costimulatory molecules by other cells of the immune system. The requirement for a second signal was proposed to prevent multivalent antigens like DNA, collagen, actin and tubulin from inducing auto-immune antibody responses.1

One candidate second signal is complement. TI-2 antigens are able to bind complement fragment C3d which is then bound to complement receptor 2 (CD21) resulting in cross-linking of membrane immunoglobulin and CD21 on polysaccharide specific B lymphocytes.18–20 This is schematically shown in Fig. 1. CD21 forms a complex with CD19, TAPA-1 and Leu-13 on B lymphocytes.21–23 Mice deficient for C3 or CD21 have an impaired antibody response to TI-2 antigens.24,25 Splenic marginal zone B lymphocytes play a very important role in the anti TI-2 immune response.26 Guinamard et al. found that in Pyk-2-deficient mice, which lack splenic marginal zone B lymphocytes, the response to TI-2 antigens was decreased in comparison to wild-type mice.27 Furthermore, the absence of splenic marginal zone B lymphocytes could provide an explanation as to why children up to the age of 2 years do not respond to polysaccharide antigens. It was found that newborn blood B lymphocytes as well as splenic marginal zone B lymphocytes of children up to 2 years of age have a reduced expression of CD21 and that acquisition of adult levels of CD21 expression coincides with onset of the anti-TI-2 response.28,29

The involvement of T lymphocytes in the immune response to TI-2 has well been established. Reconstitution of nu/nu mice with T lymphocytes resulted in an increased antibody titre against TI-2.30 Furthermore, addition of T-lymphocyte derived factors to in vitro cultured B lymphocytes enhanced the anti-TI-2 antibody response.31,32 It was further reported that CD4+ T lymphocytes enhanced and CD8+ T lymphocytes inhibited the immune response to TI-2 antigens.33–35

How do T lymphocytes influence the anti-ti-2 response?

T lymphocyte dependence of antibody response to TD antigens has intensively been investigated. TD antigens bind to B lymphocyte antigen receptors. Thereafter they are endocytosed and broken down into peptides, which are then re-expressed on major histocompatibility complex (MHC) class II molecules, where they initiate cognate interactions with antigen-specific helper T lymphocytes.36 Adhesion molecule interactions and costimulatory interactions via CD40–CD40L and B7-1/B7-2–CD28 further stabilize and enhance the cognate T/B lymphocyte interactions.36,37 The question of how T lymphocytes can influence B-lymphocyte responses to TI-2 antigens is however, largely unanswered. It seems obvious that T lymphocytes interact with B lymphocytes either directly (via cell to cell contact) and/or indirectly (via cytokines). It has, however, already been shown that TI-2 antigens do not bind MHC II molecules, excluding the possibility of a MHC II–T-cell receptor interaction.38 The potential role of other costimulatory interactions between T and B lymphocytes will be discussed in the next paragraphs. The possible interactions between B lymphocytes and T lymphocytes is schematically shown in Fig. 2.

Figure 2.

Figure 2

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Possible interactions between B lymphocytes, T lymphocytes, and antigen presenting cells (APC) and in the antibody response to TI-2 antigens (e.g. caps-PS). (a) Caps-PS activate B lymphocytes by cross-linking membrane bound immunoglobulins (mIg). Further help is provided to the B lymphocyte by T lymphocyte through costimulatory molecules. (b) Caps-PS activate B lymphocytes by cross-linking membrane-bound immunoglobulins (mIg). Further help is provided to the B lymphocyte by APC which stimulate T lymphocytes through costimulatory molecules.

CD40–CD40L

CD40 is a transmembrane molecule belonging to the tumour necrosis factor-receptor (TNF-R) family. It is expressed on B lymphocytes, monocytes and dendritic cells.39 CD40L (CD154), a member of the TNF family, is mainly expressed on CD4+ T Lymphocytes, but other cells, such as CD8+ T lymphocytes, natural killer cells, basophils and eosinophils express this molecule on their surface as well.40 The role of the CD40–CD40L is well established in the immune response to peptide antigens, whereas the role of CD40–CD40L in the immune response to TI-2 remains a matter of debate.41 It was shown that CD40 knockout mice as well as CD40L knockout mice mounted an immune response to DNP-ficoll and TNP-ficoll, both TI-2 antigens, similar to that of wild-type mice, suggesting that the immune response to TI-2 is independent of the CD40–CD40L interaction.42–44 Treatment of mice with a blocking anti-CD40L monoclonal antibody did not influence the antibody response to caps-PS.45,46 On the other hand, capsular polysaccharide (caps-PS) antigens up-regulated expression of CD40L on T lymphocytes.47,48 Furthermore, Dullforce et al. showed that administration of anti-CD40 stimulatory monoclonal antibodies together with pneumococcal capsular polysaccharides resulted in an enhancement of protective antibody levels to capsular polysaccharides in mice.49 We investigated whether CD40L plays a role in T-lymphocyte mediated regulation of the antibody response to pneumococcal capsular polysaccharides.50 Administration of MR1, an antagonist monoclonal antibody against murine CD40L, to BALB/c mice immunized with pneumococcal capsular polysaccharides resulted in an inhibition of the immunoglobulin M (IgM) and IgG antibody response to various serotypes of pneumococcal capsular polysaccharides. Evidence for the involvement of CD4+ T lymphocytes in the antibody response to pneumococcal capsular polysaccharides was further obtained in severe combined immunodeficiency (SCID/SCID) mice which, when reconstituted with B lymphocytes and CD4+ T lymphocytes mounted a higher specific IgM response compared to SCID/SCID mice reconstituted with only B lymphocytes. This helper effect of CD4+ T lymphocytes was abrogated by MR1. Also, in an in vitro system, blocking CD40L decreased the IgM response to pneumococcal capsular polysaccharides and abolished the helper effect of CD4+ T lymphocytes. CD8+ T lymphocyte-depleted murine spleen cells mounted a higher in vivo antibody response than total murine spleen cells, which provided evidence for a suppressive role of CD8+ T lymphocytes on the antipneumococcal capsular polysaccharides antibody response. CD4+ T lymphocyte-depleted murine spleen cells, leaving a B and CD8+ T lymphocyte fraction, elicited only a weak in vivo and in vitro antibody response, which was enhanced after MR1 administration. Simular results were found for the human antibody response to caps-PS. In in vivo and in vitro experiments we found that the human antibody response was regulated by CD4+ and CD8+ T lymphocytes and that the stimulatory effect of the CD4+ T lymphocytes as well as the inhibitory effect of the CD8+ T lymphocytes was mediated by the CD40–CD40L interaction (Jeurissen et al., manuscript submitted).

Taken together, our data provide evidence that T lymphocytes contribute to the regulation of the antipneumococcal capsular polysaccharides antibody response in a CD40L-dependent manner. The fact that neonatal T lymphocytes express less CD40L after stimulation with phorbol 12-myristate 13-acetate and ionomycin than adult T lymphocytes could contribute to the diminished antibody response to TI-2 antigens in neonates.51,52

Cytotoxic T lymphocyte antigen-4 (CTLA-4) (CD152)/CD28–B7-1/B7-2

CTLA-4 (CD152) and CD28 fulfil a critical role in maintaining immunologic homeostasis.53,54 CD28, which is expressed constitutively on T lymphocytes, mediates a positive signal through binding to B7-1 and B7-2 expressed on B lymphocytes.54 CTLA-4, a close relative of CD28, binds B7-1 and B7-2 ligands on B lymphocytes and dendritic cells with an affinity approximately 20-fold higher than that of CD28.55 In contrast to CD28, CTLA-4 is rapidly up-regulated after T-lymphocyte activation and is a negative regulator of T-lymphocyte activation.56 Once CTLA-4 expression is up-regulated following T-lymphocyte activation, the inhibitory B7–CTLA-4 interaction predominates, leading to the termination of T lymphocyte activation.56 The critical role of CTLA-4 in down-regulating T-cell activation was shown in CTLA-4-deficient mice. These mice develop lymphoproliferative disease and die by 3–4 weeks of age.57,58 Blocking of this inhibitory signal by monoclonal antibodies to CTLA-4 was already shown to enhance antitumour responses.59 Sutmuller et al. reported that blocking of CTLA-4 together with depletion of CD25+ T regulatory lymphocytes resulted in tumour rejection.60 Furthermore, blocking CTLA-4 resulted in an increased immunity to nematode infection (Nippostrongylus brasiliensis).61

We found that anti-CTLA-4 treatment using monoclonal antibodies resulted in a dose-dependent enhancement of an isotype switched and highly protective polysaccharide-specific antibody response (Boudewijns et al., manuscript submitted). This provides evidence that CTLA-4 plays a down-regulating role in the immune response to TI-2 and that anti-CTLA-4 treatment can potentially be used as immunological adjuvant in vaccination strategies.

The role of CD28 in the antibody response to TI-2 antigens is less clear. Wu et al. found that CD28 knock out mice generated significantly diminished IgG antiphosphorylcholine in comparison to wild-type mice when injected with the non-encapsulated variant of type 2 Streptococcus pneumoniae.62

4-1BB−4-1BBL

4-1BB, another member of the TNF-R family, is not expressed on resting T lymphocytes, but can be up-regulated on activated T lymphocytes.63,64 Its ligand, 4-1BBL, is expressed at low levels on resting B cells and up-regulated on activated B lymphocytes and monocytes.65 Signalling via 4-1BB preferentially costimulates CD8+ T lymphocytes.66 Upon binding of 4-1BB agonistic monoclonal antibodies, cytotoxic activity and interferon-γ (IFN-γ) secretion by CD8+ T lymphocytes is increased.66,67 The role of the 4-1BB−4-1BBL interaction in the immune response to TI-2 is controversial. Administration of an agonistic anti4-1BB monoclonal antibody had no effect on the pneumococcal anti-cell wall polysaccharide response.68 However they used intact non-capsulated Streptococcus pneumoniae as an antigen, which is in fact not a real TI-2 antigen. Using 4-1BB-deficient mice and agonistic 4-1BB monoclonal antibodies Kwon et al. concluded that the 4-1BB−4-1BBL interaction does not play a role in the immune response to TNP-ficoll, a TI-2 antigen.69,70

BlyS/APRIL–TACI/BCMA/BAFF-R

The B lymphocyte stimulator (BLyS, also called TALL-1, THANK, BAFF, zTNF4) is expressed by macrophages, monocytes and probably by dencritic cells and T lymphocytes. There are three receptors for BlyS: TACI, BCMA, and BAFF-R and they are all expressed on B lymphocytes.71,72 BAFF-R appears to mediate most of the B lymphocyte survival signals elicited by BlyS.73 APRIL (a proliferation-inducing ligand, also called TRDL-1), a close relative of BLyS and also belonging to the family of the TNF-like ligands, is expressed on activated T lymphocytes and interacts with TACI and BCMA, but not with BAFF-R.73,74 Evidence is accumulating for the existence of at least one specific receptor for APRIL (APRIL-R), as the Jurkat human leukaemia T-cell line is susceptible to APRIL stimulation, but not to BlyS, and neither BCMA nor TACI were detectable by reverse transcription–polymerase chain reaction in Jurkat cells.75

BlyS ligation is known to induce both in vivo and in vitro B lymphocyte proliferation and differentiation, and transgenic animals overexpressing BLyS have increased numbers of mature B lymphocytes.76–78 However, they develop autoimmune-like manifestations such as the presence of high levels of rheumatoid factors, circulating immune complexes, anti-DNA antibodies and immunoglobulin deposition in the kidneys.79 In APRIL transgenic mice, however, there was no increase in the B lymphocyte compartment.80 It was shown that APRIL transgenic mice had an increased immune response to TI-2 in comparison to wild type mice.79 BAFF-R-deficient mice had a normal immune response to TI-2 in comparison to control animals.80 TACI knockout mice on the other hand, had a diminished immune response to TI-2.79 These findings suggest that the APRIL/BlyS–TACI interaction participates in TI-2 humoral immune responses. It has been postulated that BLyS as well as APRIL increase the number of marginal zone B lymphocytes and thereby influence the immune response to TI-2.71,79

Ox40–Ox40L

Ox40 (CD134) is a member of the TNF-R family, which is expressed by activated T lymphocytes.82 Its ligand is a member of the TNF family and is expressed on numerous activated immune system cell types, including dendritic cells, B lymphocytes and T lymphocytes.82 Ox40 signals are a potent source of costimulation for a developing primary CD4+ T lymphocyte response, and the major action is during the late phase response promoting continued proliferation and expansion of effector cells.83 Chen et al. found that the antibody response to TD antigens in Ox40L knockout mice was not significantly different from the antibody response in wild type mice.84 Only scarce information is available on the role of the Ox40–Ox40L interaction in the antibody response to TI-2 antigens. Stüber et al. showed that administration of anti-Ox40 monoclonal antibody to mice inhibited the immune response to TD antigens but not the antibody response to TI-2 antigens.85

Cytokines

Using human peripheral blood cells Leiva et al. reported that TI-2 antigens up-regulated IL-4 production in vitro.48 Other investigators found that in murine spleen TI-2 antigens stimulated interleukin (IL)-2, IL-4, and IFN-γ production by T lymphocytes.47 A cytokine that seems to play a special role in the antibody response to TI-2 antigens is IL-12. Buchanan et al. demonstrated that administration of IL-12 in mice together with TI-2 antigens significantly enhanced the antibody response. This enhancement was independent of natural killer cells and T lymphocytes.86 It is also known that IL-12 enhances functional CD40L expression on T lymphocytes.87 Considering the fact that the CD40–CD40L interaction plays a role in the immune response to TI-2 antigens, the question remains whether the stimulatory effect of IL-12 on the antibody response to TI-2 antigens is mediated by up-regulation of CD40L.

How is the immune system activated by TI-2 antigens?

If T lymphocytes play a major role in the humoral immune response to TI-2, the question remains how T lymphocytes are activated by TI-2 antigens. Up till now, neither processing nor presentation by MHC class II molecules has been demonstrated for TI-2 antigens.38 CD1, which shows striking similarities to MHC I proteins, is a possible molecule to present polysaccharides to T lymphocytes.88 In man, CD1 molecules are expressed on specialized antigen presenting cells and are required for the presentation of antigens from mycobacteria to T lymphocytes.89,90 Besides, CD1 also plays a role in the presentation of lipids and glycolipids to T lymphocytes. Recently, CD1 has been suggested as a candidate transmembrane molecule by which polysaccharides could be presented to T lymphocytes.91–93 Lee et al. showed that β2-microglobulin gene knockout mice, which lack CD1 and MHC class I molecules, did not produce IgG antibodies to pneumococcal capsular polysaccharide in response to a pneumococcal polysaccharides vaccine, but these mice were still responsive to the protein-conjugated vaccine.94 However, to confirm a role of CD1, experiments should be conducted using anti-CD1 monoclonal antibodies and mice who are only deficient for CD1 and not for MHC class I molecules.

Other candidates via which T lymphocytes could be activated in the antibody response to TI-2 antigens are the Toll-like receptors (TLR). TLR are expressed on antigen-presenting cells.95 TLR-mediated recognition of microbial components induces expression of costimulatory molecules and production of cytokines.96 So far, 10 mammalian TLR have been identified.97 Individual TLR recognize distinct structural components of pathogens.97 TLR4 for instance recognizes lipopolysaccharides from Gram-negative bacteria.98 Until now, the role of TLR in the antibody response to TI-2 antigens is mainly unknown. There is however, some indirect evidence that TLR might play a role in the antibody response to TI-2. Echchannaoui et al. found that TLR-2 deficient mice had a reduced survival time after intracerebral inoculation with S. pneumoniae.99 Koedel et al. found that after infection with S. pneumoniae, the number of micro-organisms in the cerebellum and blood was higher in TLR2-deficient mice than in wild-type mice.100 Other investigators found that after nasopharyngeal exposure of pneumolysin-producing S. pneumoniae, TLR4-deficient mice had a significantly increased mortality compared with control mice.101

Others have suggested that T lymphocytes can be recruited directly by multivalent TI-2 antigens without the requirement of antigen presentation or that B lymphocytes would recruit T lymphocytes without TCR triggering.14

Conclusion

The role of T lymphocytes in the antibody response to TI-2 antigens is more important than was first thought, and there now is convincing evidence that T lymphocytes support the antibody response to TI-2 antigens via several pathways including the CD40-CD40L pathway. Despite this, it remains enigmatic how T lymphocytes are recruited in the immune response to TI-2 antigens and identification of this process is a major challenge for further research.

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