Mechanism of Thymus-Independent Immunocyte Triggering

Abstract

We have suggested before that thymus-independent immune responses to certain antigens are caused by special properties of the antigens concerned, namely that they are B-cell mitogens (1). Actually all thymus-independent antigens (TI) 1 we have tested so far were found to be competent to activate DNA and polyclonal antibody synthesis in nonprimed B cells cultured in vitro (2). Since the TI antigens can directly induce division and differentiation in B cells, it is evident that T-B cells cooperation would not be required for the induction of specific immune responses. However, there is an apparent paradox between the ability of a mitogen to induce an antigen-specific immune response to its own antigenic determinants, and its ability to activate polyclonal antibody synthesis in all B cells, irrespective of their specificities. The paradox can be easily explained by assuming two fundamentally different types of antigen binding to the cell surfaces. At low (immunogenic) concentrations, TI antigens would be preferentially bound by lg receptors on specific antigen-binding B cells, whereas at high (mitogenic) concentrations also, other B cells (lacking specific receptors for the antigenic determinants of these molecules) would bind a sufficient number of molecules to become activated. Once triggering concentrations were reached on the cell surface, the cell would be activated and secrete the immunoglobulin for which it is genetically programmed. In terms of this argument, T-cell independence could be considered the most sensitive test for B-cell mitogenicity, since it is the "physiological" expression of direct B-cell activation.The present experiments were designed to test this hypothesis critically, by use of the hapten 4-hydroxy-3,5-dinitrophenyl (NNP) coupled to the B-cell mitogen lipopolysaccharide (LPS) (3).

Toll-like receptor 4-mediated signaling regulates IL-7-driven proliferation and differentiation of B-cell precursors

“…24 Recent studies by Hayashi et al indicate that TLR4 signaling also plays a role during late stages of B-cell development by facilitating the generation of immature or transitional B cells. 14 The present study further demonstrates that early B-cell development is subject to regulation by TLR4 signaling.…”

TLR Agonists Selectively Promote Terminal Plasma Cell Differentiation of B Cell Subsets Specialized in Thymus-Independent Responses

“…This observation gave ground to the idea that microbial products could contribute to maintain a crucial function of the immune system. In the mouse, naive B cells proliferate and secrete Igs in response to LPS and CpG (11,12), indicating that they express functional TLR4 and TLR9. However, little is known about the distribution of TLRs and the impact of their agonists on mouse naive B cell subsets.…”

“…Their most common natural or synthetic agonists include peptidoglycan and Pam 3 CSK 4 (TLR1/2), bacterial lipoproteins and MALP2 (TLR2/6), dsRNA and poly(I:C) (TLR3), LPS (TLR4), flagellin (TLR5), ssRNA and imidazoquinolines (TLR7 and TLR8), unmethylated CpG oligodeoxynucleotides (TLR9), and profilin-like molecule (TLR11) (7)(8)(9)(10). It has long been known that certain TLR agonists can deliver B cell stimulatory signals (11,12). Furthermore, Ruprecht and Lanzavecchia (13) demonstrated that TLR stimulation is required along with BCR triggering and T cell help to sustain optimal proliferation and differentiation of human naive B cells.…”

Difference in Genesis between Antigen‐Induced IgM Antibody‐Forming Cells and B‐Cell Mitogen‐Induced IgM Antibody‐Forming Cells in Mouse Spleen Cell Cultures

“…On the role of helper T cells in the genesis of IgM AFC by stimulation with T-dependent antigen, Mäller and his colleagues (3,17) assumed that signal from helper T cells or their factor (s) for B cell activation should be similar to that from ANTIGEN-INDUCED AFC AND MITOGEN-INDUCED AFC 165 B-cell mitogen, although Dutton and Hunter (6), and Schimpl et al (19) regarded the "T-cell-replacing factor" as mediator for the differentiation signal as described. The assumption of Moller's group appears to be corroborated by the fact that nu/nu spleen cells, being devoid of T cells, responded to SRBC under simultaneous stimulation with B-cell mitogen.…”