The complement system is important not only in humoral immunity; it also enhances responses by both CD4 + and CD8 + T cells. Studies with influenza in C3-deficient mice first identified an important role for C3 in both the CD8 + and CD4 + response to infectious virus. Although this was initially thought to be dependent on serum-derived complement components, similar to the observations referred to in a previous section that the humoral immune response in C1q −/−, C4 −/−, and C3 −/− mice could be reconstituted by BM-derived immune cells locally producing complement components, so too it was found that antigen-induced Th1 cell activation in CD4 + T cells was serum complement-independent, but was instead dependent on C3, C5, FB, and FD being expressed and secreted by both the antigen-presenting cell (APC) and the T cell. C3a and C5a produced by extracellular C3 and C5 convertases bind to their respective C3aR and C5aR1 receptors on the APC and to C3aR on the T cell in an autocrine/paracrine manner, leading to maturation of both partners as evidenced by their cytokine production. In humans, autocrine engagement of the complement regulatory protein CD46 on the T-cell surface by T-cell-produced C3b is also required for the induction of a Th1 phenotype of CD4 + T cells. It should be noted that CD46 is a signaling receptor, as both of its differentially spliced cytoplasmic tails (Cyt-1 and Cyt-2) are substrates for kinases. Notably, mice do not express CD46 on hematopoietic cells, but a case has been made that one or more members of the Notch receptor family are the functional homologs to CD46 in mice.

Before outlining the main features of the current working model for complement’s role in the human CD4 + Th1 response, at present the best understood area of complement’s involvement in T-cell immunity, there is one additional site of complement activation involving T cells to consider, specifically the intracellular complement system, sometimes referred to as the complosome. Although sharing with the extracellular complement system the presence of the anaphylatoxin receptors C3aR and C5aR1, the engagement of these receptors by their respective ligands intracellularly results in distinct signaling pathways and cellular responses compared to those that occur when engagement is at the cell surface. Intracellular complement activation is essential for both the maintenance of resting CD4 + T cells, as well as their activation to a Th1 phenotype. In the resting cells, an intracellular (endosomal and lysosomal) source of C3 is continuously cleaved into C3a and C3b by the lysosomal endoprotease cathepsin L (CTSL). Engagement of lysosomal membrane-resident C3aR by intracellularly-generated C3a provides a survival signal for such resting T cells via the activation of mTOR (mammalian target of rapamycin). Indeed, inhibition of CTSL proteolytic activity results in the resting T cells undergoing apoptotic death. Upon activation of CD4 + cells via their T-cell receptor (TCR), the intracellularly-generated C3a and C3b translocate to the cell surface where they engage their respective receptors C3aR and CD46. Although the protease is as yet unknown, intracellular C5 also undergoes cleavage to produce C5a as a ligand for intracellular C5aR1 (organellar location at present unknown), whose ligation results in an increased production of mitochondrial-derived reactive oxygen species (ROS). The ROS triggers the assembly of the NLRP3 inflammasome, which in turn initiates caspase-1-dependent IL-1 β secretion.  Collectively these autocrine events are crucial for the induction of an IFN- γ -producing Th1 phenotype. Since C3 and C5 are normally exported from the cell via the secretory pathway, their intracellular presence requires either importation from the extracellular milieu, or some form of retrotranslocation from the organelles of the secretory pathway. In the case of C3, it has been suggested that C3(H 2O), the thioester-hydrolyzed form of the protein, is imported from the extracellular milieu in the course of a receptor-specific recycling process, whereupon the non-re-exported portion of C3(H 2 O) is cleaved into C3a and C3b by CTSL.

As an indication of the importance of CD46 in T-cell functionality, patients deficient in CD46, like those deficient in C3, suffer recurrent infections and when their CD4 + T cells are stimulated in vitro with anti-TCR and anti-CD28, they fail to secrete IFN- γ , which is typical of Th1 response, but do secrete normal levels of Th2 response cytokines IL-4 and IL-5.

After successful Th1 expansion leading to pathogen clearance, there is “tune down” of the Th1 response that is required for maintenance of immune homeostasis. Such contraction of the Th1 response involves ligation of CD46 in concert with the binding of the cytokine IL-2 to its receptor, where the latter cytokine would have accumulated to fairly high concentrations during the successful expansion of the Th1 response. This leads to switch from the effector Th1 phenotype to a Treg-like phenotype, including upregulation and secretion of the regulatory cytokine IL-10.

In contrast to the CD4 + T-cell situation, much less is mechanistically known about the role of complement in CD8 + T-cell responses. A recent report found that, although CD8 + T cells possess much of the same autocrine complement, complosome, and inflammasome activities described for CD4 + T cells, whereas CD46-mediated signals are obligatory for Th1 differentiation by CD4 + T cells, they are not obligatory for basal level effector functions in CD8 + T cells, but are critical for optimal cytotoxic activity by these cells .

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إزالة ثاني أكسيد الكربون من الغلاف الجوي.. ما دور المحيطات والبحار؟

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مواضيع ذات صلة

Complement and Cancer

Focusing Antigen on Follicular Dendritic Cells

B-Lymphocyte Coreceptors

The Complement System : Alternative Pathway

The Complement System : Lectin Pathway

The Complement System: Classical Pathway

Secondary Lymphoid Tissue

The Hematopoietic Microenvironment

The Pro-B- and Pre-B-Cell Checkpoints

Immunoglobulin Gene Rearrangement : Heavy Chain Gene Rearrangement

Transcriptional Regulation of B-Cell Development

Stages of B-Cell development