Abstract
Although originally identified as a B cell differentiation factor, it is now known that mammalian interleukin-6 (IL-6) only regulates B cells committed to plasma cells in response to T-dependent (TD) antigens within germinal centers (GCs). Even though adaptive immunity is present in teleost fish, these species lack lymph nodes and GCs. Thus, the aim of the present study was to establish the role of trout IL-6 on B cells, comparing its effects to those induced by bacterial lipopolysaccharide (LPS). We demonstrate that the effects of teleost IL-6 on naïve spleen B cells include proliferation, activation of NF-κB, increased IgM secretion, up-regulation of Blimp1 transcription and decreased MHC-II surface expression that point to trout IL-6 as a differentiation factor for IgM antibody-secreting cells (ASCs). However, LPS induced the secretion of IgM without up-regulating Blimp1, driving the cells towards an intermediate activation state in which antigen presenting mechanisms are elicited together with antibody secretion and expression of pro-inflammatory genes. Our results reveal that, in trout, IL-6 is a differentiation factor for B cells, stimulating IgM responses in the absence of follicular structures, and suggest that it was after follicular structures appeared that this cytokine evolved to modulate TD responses within the GC.
Highlights
The immune system comprises both innate and adaptive immune responses
We found that IgM+ B cells from all three tissues constitutively transcribed IL-6Rαand gp[130] at similar expression levels (Supplemental Figure S1A), suggesting that naïve B cells have the capacity to respond to Interleukin 6 (IL-6)
Mammalian IL-6 exclusively signals in antigen-experienced cells[15], only affecting the outcome of switched antibody isotypes such as IgG or IgA18,19,48; a recent study reported that fugu (Takifugu rubripes) unstimulated B cells transcribe both IL-6Rαand gp[130] and that the in vitro stimulation of blood leukocytes with IL-6 up-regulates IgM transcription levels[42]
Summary
The immune system comprises both innate and adaptive immune responses. While the innate immune system is genetically programmed to detect invariant features of invading microbes, the cells of the adaptive immune system, such as conventional B cells (B2) and T cells, detect specific epitopes through somatically recombined receptors. Conventional B cells are activated in response to T-dependent (TD) antigens within the lymphoid follicles and trigger the formation of germinal centers (GCs) These sites promote the close collaboration between proliferating antigen-specific B cells, T follicular helper cells, and the specialized follicular dendritic cells (DCs) that constitutively occupy the central follicular zones of secondary lymphoid organs. In this environment, B cells divide in response to antigens and acquire the capacity to differentiate into antibody-secreting cells (ASCs), reaching a terminal state of plasma cells or memory B cells, both of them with the capacity to secrete high affinity antibodies. TLR4 is thought to be absent from the genome of salmonid fish[26], some effects of LPS on salmonid B cells have been reported[27]
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