服务生命科学/serve life science

Lymphocytes T (or T cells) are key mediators of adaptive immunity, the part of the immune system capable of generating a pathogen-specific, long-lasting defense mechanism (for an overview on the topic check out Tools to study adaptive and innate immune response). The specificity of the T cells response is related to the antigen-specific receptors they express, the TCRs (T Cell Receptor). While each lymphocyte T is characterized by the expression of thousands of identical TCRs, the global repertoire of TCRs in the organism is dramatically varied, so that these cells can recognize (and respond to) virtually any intruders. Similar to the immunoglobulins expressed by B cells, TCRs are somatically-generated and their diversity is obtained by random rearrangements of their gene segments. T cells only recognize antigens once these have been processed into peptides and exposed onto the surface of the target cell, in an antigen presentation structure known as the Major Histocompatibility Complex (MHC). The MHC-antigen complex binding to the TCR is the first, mandatory step for T cell activation.

MHC molecules are cell surface glycoproteins classified as class I or class II

MHC Class I can be found in all nucleated cells. In physiological conditions, this complex exposes peptides generated by the normal turnover of endogenous proteins. These “self” peptides will not trigger lymphocyte T activation. On the contrary, following for example virus infection, the viral proteins will also be processed in the cytoplasm and then exposed on the cell surface, inducing T cell activation.

MHC Class II is only present on professional Antigen Presenting Cells (APCs) such as macrophages, dendritic cells, and B cells. Once a pathogen has been recognized, engulfed, and digested by these specialized cells, their MHC class II complex will present these exogenous antigens to the T cells, eliciting their activation.

If the interaction between the TCR and the MHC complex is necessary for T cell response, it is certainly not sufficient. First of all, the TCRs are not the only receptors expressed on T cell membranes. In fact, two major lymphocyte T subsets are distinguished based on the presence of CD8 or CD4 co-receptors: cytotoxic T cells express the first (CD4^–/CD8⁺ cells), whereas T-helper cells (Th) express the second (CD4⁺/CD8- cells).

Cytotoxic T cells recognize antigenic epitopes presented by MHC class I molecules. Upon this interaction, clonal cytotoxic T cells differentiate into effector cells, which in turn secrete perforin, granzyme (a protein that causes lysis of target cells), and granulysin (a substance that induces apoptosis of target cells). Therefore, as suggested by their name, they directly destroy the infected cell.

T helper cells instead, following their interaction with the MHC Class II on the APC, proliferate and differentiate, eventually modulating the activity of other immune cells through cytokine production or via cell-to-cell contact. Until they encounter the complex MHC-peptide, the naïve CD4+ Th cells are uncommitted and have the potential to differentiate into subgroups, such as Th1, Th2, Th17, Thf (T follicular helper), each characterized by the secretion of a specific cytokine profile.

Th1 and Th2 cells

Given the crucial role of Th1 and Th2 in the immune response, the mechanisms leading to the priming of naïve CD4+ T cells into Th1 or Th2 have been investigated for a long time. Some information may still be missing, but it is clear that the cytokine microenvironment is fundamental in the process, as well as the strength of the stimulatory signals from the APC (i.e. affinity of TCR for the peptide ligand).

The most critical interleukins required for Th1 differentiation are IL-12 and IFN-y. IL-12, secreted by the APCs in response to Toll-like receptor stimulation, leads to the expression of the transcription factor STAT-4, in turn inducing the production of IFN-y. This creates a positive loop, involving STAT-1 and T-bet. T-bet is considered a master regulator of Th1 cells as it further boosts IFN-y expression; promotes IL-12 response by upregulating the IL-12 receptor; inhibits the progression towards the Th2 lineage silencing IL-4 expression and impairing the function of the Th2 master regulator GATA3.

Once differentiated, Th1 effector cells are characterized by the production of pro-inflammatory cytokines such as IFN-γ, TNF-α, and IL-2, capable of stimulating the macrophages, the NK cells, CD8+ cytotoxic T cells, against intracellular pathogens. In addition, Th1 response is involved in tumor clearance, via the activation of CD8+ cytotoxic T lymphocytes. The deregulation of the Th1 response has been associated with autoimmune diseases.

Th2 cells are implicated in the defense against extracellular parasites (e.g. helminths) and the stimulation of the humoral response (via the B cells). In pathological conditions, these cells are responsible for several inflammatory conditions, such as allergic reactions, asthma, atopic dermatitis, etc.
The key interleukin for Th2 polarization is IL-4, which drives STAT-6 phosphorylation and the consequent upregulation of the master transcription factor GATA-3. The latter promotes Th2 response inducing the selective growth of Th2 cells, inhibiting Th1 cell-specific factors, and stimulating the production of the interleukins mediating Th2 cell action. For example, IL-4, IL-5, and IL-13 contribute to B cell proliferation and isotype class switching from immunoglobulin IgG1 to IgE, a key antibody involved in parasitic helminth infection

The table below indicates the main differences between Th1 and Th2 cells.