1.3.2 Progress of Activated Immune Cells [17]
A lot of studies have shown that self-antigen or tumor antigen-specific CD4+ and CD8+ T cells are present in healthy individuals.How such self- or tumor-reactive T cells are controlled in healthy or tumor-bearing individuals remains to be determined.Mechanisms for the maintenance of immunological self-tolerance (i.e., unresponsiveness to self-antigens) not only prevent autoimmunity but also hamper effective tumor immunity because many tumor antigens recognized by autologous lymphocytes are normal self-antigens or quasi-self-antigens with genetic mutations.This is one reason why it is difficult to elicit strong tumor immunity in cancer-bearing patients by cancer vaccine alone.It also suggests that effective tumor immunity can be evoked by breaching a certain mechanism(s) of immunological self-tolerance systemically or locally in tumor tissues.
On the one hand, among the various mechanisms of immunological self-tolerance, immune suppression by endogenous Foxp3+CD25+CD4+ Treg cells is essential and indispensable as illustrated by spontaneous autoimmune disease development when Treg cells are rendered deficient.For example, mutations of the gene encoding the Treg-specific transcription factor Foxp3 impair Treg cell development and cause a fatal multi-organ autoimmune disease called immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome.Depletion of Foxp3+CD25+CD4+ Treg cells by a variety of methods is also able to cause similar autoimmune diseases in otherwise normal rodents.
On the other hand, it is now well substantiated that a large number of Treg cells infiltrate into tumor tissues of various cancers and their abundant presence is often associated with poor clinical prognosis.Experimentally, the role of Treg cells in tumor immunity was first demonstrated by an attempt to determine a common basis between tumor immunity and autoimmunity.Removal of Treg cells using cell-depleting anti-CD25 antibody, either by in vivo antibody administration to mice or transfer of cell suspension depleted in vitro of CD25+ Treg cells into histocompatible T-cell-deficient mice, effectively eradicated a variety of inoculated syngeneic tumors.The mice showed an increase of tumor-infiltrating CD8+ T cells with strong tumor-specific killing activity,and upon re-challenge with the same tumor cells, exhibited more rapid rejection than the primary rejection, indicating the establishment of tumor-specific immunity.These studies have thus demonstrated that the removal of Treg cells is able to evoke effective anti-tumor immunity by abrogating immunological unresponsiveness to syngeneic tumors, albeit it may also cause autoimmunity, especially if Treg cells are depleted systemically.(https://www.daowen.com)
The T-cell receptor (TCR) repertoire of Treg cells is broad and skewed to a certain extent to recognizing self-antigens.That is, in the course of T-cell selection in the thymus, a developing Treg cell exhibits a higher TCR affinity than a conventional T (T conv) cell for the MHC/self-peptide ligand that selects both.Assuming that TCR recognition of peptides is cross-reactive (and degenerate) and a particular TCR is able to recognize a million different peptides of 10 amino acid length, the TCR repertoire of Treg cells as well as T conv cells is broad and able to recognize a wide spectrum of self and non-self-antigens including quasi-self-tumor antigens.Given the antigen-primed state of endogenous Treg cells (as illustrated by higher level expression of T-cell accessory molecules such as LFA-1), it is reasonable to assume that Treg cells recognizing a particular self- or tumor- antigen are more easily activated than naive T conv cells recognizing the same antigen, ensuring Treg-mediated dominant tolerance.
Treg cells would be able to control not only T cells but also B cells, NK cells, dendritic cells (DCs),and macrophages via humoral and cell-cell contact mechanisms.A variety of molecules are involved in Treg-mediated suppression mechanisms, including CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), IL-2, IL-10, TGF-β, IL-35, GITR (glucocorticoid-induced TNF receptor), LAG3 (lymphocyte-activation gene 3), granzyme B, adenosine, and cAMP (Figure 1.2).Given that ectopic Foxp3 expression in T conv cells would be able to confer Treg-like suppressive activity, the molecule(s) mediating a core suppressive mechanism may well be controlled by Foxp3.In addition, among various mechanisms of Treg-dependent suppression, those important for maintaining self-tolerance (i.e., the suppression mechanisms whose impairment causes autoimmune disease) have the most impact on tumor immunity.On these assumptions, there are only a few molecules whose expression is controlled by Foxp3 directly or indirectly and whose deficiency abrogates Treg-suppressive function and causes severe autoimmune diseases.The candidates include IL-2, IL-2 receptor subunits, and CTLA-4.Foxp3 indeed controls the expression of these molecules and deficiencies of IL-2, CD25 (IL-2 receptor α-chain), and CD122 (IL-2 receptor β-chain), or CTLA-4 produces similar autoimmune diseases as observed in Foxp3 deficiency.
Figure 1.2 Treg suppression mechanisms.Treg cells, which scarcely produce IL-2, deprive IL-2 from the surrounding via their high affinity IL-2 receptor, making it unavailable for responder T cells.They also constitutively express CTLA-4, which down-modulates CD80/CD86 expression by antigenpresenting cells (APCs), thus depriving co-stimulatory signal to responder T cells.Treg cells also produce immune-suppressive cytokines such as IL-10, which also down-modulates APC functions.Under this deprivation of co-stimulatory signal, responder T cells with high-affinity TCRs for the presented antigen die by apoptosis, those with intermediate affinity TCRs are rendered anergic, and those with low-affinity TCRs stay dormant.This IL-2/IL-2 receptor-dependent and CTLA-4-dependent mechanism forms a core basis of Treg-mediated suppression in various tissues including cancer.
Source: Tanaka A, Sakaguchi.“Regulatory T Cells in Cancer Immunotherapy”.CellResearch, 2017,27(1):109-118.