With great interest we have read the recent paper by Khan et al. (1) on the cognate T cell help in the immune response to intact Streptococcus pneumoniae. The authors studied the role of the CD4+ T cells on the IgM and IgG responses specific for the capsular polysaccharide, the cell wall C-polysaccharide, and the pneumococcal surface protein A. In their manuscript they state that, “in responses to intact S. pneumoniae, IgG responses to capsular polysaccharide are strongly dependent on CD4+ T cells and CD40L-dependent costimulation, unlike responses observed for purified soluble polysaccharide Ags”.
Pneumococcal capsular polysaccharides (caps-PS) are classified as T cell-independent Ags type 2 (2). These Ags stimulate Ab production in the absence of MHC class II restricted T cell help, but, nonetheless, they can recruit T cell help (2). It has been previously demonstrated that T cells play a role in the anti-caps-PS Ab response (3, 4). More recently, we showed that the Ab response to soluble caps-PS is dependent on T cells and on the CD40-CD40L interaction (5, 6). Besides, Dullforce et al. (7) showed that administering anti-CD40 mAb to mice along with pneumococcal polysaccharide results in the generation of a strong protective Ab response.
Therefore we think that, contrary to what is claimed by Kahn et al. and to previous observations (8), there is presently enough evidence to state that T cells and CD40-CD40L interaction play a role in the Ab response to caps-PS.
The Authors Respond
The letter by Drs. Jeurissen and Bossuyt challenges the veracity of a statement we made in our recent paper by Khan et al. (R1 ) that IgG responses to purified TI-2 (polysaccharide) Ags are T cell independent, unlike the IgG anti-polysaccharide responses that we observe upon challenge with intact extracellular bacteria, which are critically dependent on CD4+ T cells. They cite their own recently published work (R2 ) and that from B. J. Zegers’ lab (R3 ), although they omit citing the much earlier extensive work from P. J. Baker’s group (for review see Ref.R4 ), that collectively demonstrate the existence of T amplifier (Ta) and T suppressor (Ts) cells in response to certain purified TI-2 Ags. Indeed, on this basis Jeruissen and Bossuyt wish to conclude that, “the Ab response to soluble capsular polysaccharide is dependent on T cells”. However, as summarized by Baker and Hiraba (R4 ): “Although both types of regulatory T cells are activated after exposure to Ag, their activities are usually counterbalanced. This balance explains why athymic mice make nearly the same Ab response to SSS-III as thymus-bearing mice, and why Ts and Ta have escaped detection for so many years.” Hence, these responses may involve the activation of Ta and Ts cells, but are not collectively dependent on these T cells, a point confirmed through the use of athymic nude or TCR-knockout mice. Our use of the traditional expression “T cell-independent” follows this latter widely accepted understanding (R5 ). In this regard, our observations that IgG anti-polysaccharide responses to intact S. pneumoniae are markedly reduced in athymic nude or TCR-knockout mice, whereas the Ig responses to purified polysaccharide Ags are not (R1 R6 ), underscores a very important mechanistic distinction between these two types of “immunogen”, but does not in any way contradict the many studies on Ta and Ts cells.
The recently published study by Jeurissen and Bossuyt (R2 ) which reports a role for CD40/CD40L interactions in Ig responses to purified pneumococcal polysaccharide (PPS)3, 4, and 19F, while interesting, stands in contrast to many previous studies using the TI-2 Ags, TNP-Ficoll, or DNP-Ficoll (R7 ), or a more recent study using purified PPS6B (R8 ), that conclude that these Ig responses are independent of CD40/CD40L interactions. The observation that injection of an agonistic anti-CD40 mAb, a potent activator of B cells, DC and macrophages, enhances an in vivo Ig response to a purified TI-2 Ag does not address a potential endogenous role of CD40/CD40L interactions in these responses. Thus, we disagree with the general statement by Jeurissen and Bossuyt that, “there is presently enough evidence to state that … CD40-CD40L interaction[s] play a role in the Ab response to [purified TI-2 Ags]”. Instead, the differences between their published study, and those of others need to be resolved, and thus we should consider this issue as currently controversial.