CD4+ T cells play a pivotal role in the establishment and maintenance of the adaptive immune response. In peripheral lymphoid organs, Tnais can differentiate into functionally different subsets. Each subset tends to promote self-development and inhibit the differentiation of the other subsets. The competition results in one subset dominating over the others. Apart from the intracellular status of Tnais, many milieu factors may be involved in the differentiation. There is no doubt that properties of antigen-loaded antigen-presenting cells (APCs), such as the expression patterns of cytokines and costimulation molecules, can directly influence T-cell differentiation. The characteristics of the classical MHC II-restricted antigens and the concomitant non-antigenic components (e.g., endogenous or exogenous adjuvant, innate immunity-associated molecules and antibodies) and the capture mode of antigens by APCs (e.g., antigen dose, soluble or particular antigens, antigens from apoptotic or necrotic cells) may be the elements that initially determine the functional status of APCs. The subsequent but even more important factors may develop from activated memory T cells. Subsets of memory T cells may affect Tnai differentiation through both indirect effects on APCs and direct effects on Tnais via cytokine release or cell contact. The effects are essential for adaptive immune memory because of the lack of evidence for the existence of professional antigen-specific memory APCs. If adaptive immunity has been established, antigen-specific memory T-cell subsets are activated primarily by the invading antigens, and the memory status is maintained by facilitating Tnai induction into the same T-cell subsets.
Although antigen-specific memory mediated by T cells is central to the adaptive immune response, antigen-non-specific interaction among T-cell subsets may also play an important role in two situations. The first is when antigens are encountered for the first time, when no antigen-specific memory T cells are yet present. The second is when several antigens are presented closely—both temporally and spatially—to different T-cell subsets. Hence, we propose the antigen non-specific model for the induction of Tregs (). The key point of this model is that, regardless of antigen specificity, the component ratio of activated T-cell subsets and their temporal and spatial uniformity largely determine Tnai differentiation. If activated Tregs outnumber activated Teffs, Tnais preferentially differentiate into Tregs, 4
and vice versa
During an individual’s lifespan, the peripheral immune system is continually exposed to new endogenous and exogenous antigens. In this setting, there are very few, if any, memory Tregs and Teffs specific for newly encountered antigens. The number of activated Tnais is proportional to the dose of the priming antigens. The number of activated Tregs is determined mainly by the base level of activated Tregs, as well as by the dose and memory status of the concomitant antigens, which also determine the number of activated Teffs. In most cases, newly encountered antigens represent only a fraction of a complex mix of antigens. The concomitant antigens are regarded as making up the remaining portion of the mixed antigens, but they can be presented to the specific memory T-cell subsets.
Figure 1 Antigen-non-specific control of differentiation of Tnais. Mixed antigens are temporally and spatially closely presented to T-cell subsets in the peripheral lymph nodes. Regardless of antigen specificity, when activated Tregs outnumber activated Teffs, (more ...)
With respect to tumor cells, newly mutated neo-antigenic peptides and normal cell components are presented to T cells concurrently. The low ratio of mutated tumor antigens to normal cell components, and the preferential recognition of the latter antigens by Tregs, may contribute to the induction of tolerance to tumor cells during the very early stages of oncogenesis. Chronic infection, especially intracellular infection, is more favorable than acute infection for the induction of tolerance because of the decreased level of foreign antigens and the increased level of antigens resulting from the infected tissues (necrotic or apoptotic tissue cells). In addition to antigens, cytokines produced in the tumor and inflammatory milieu determine the fate of Teffs and Tregs. In acute inflammation, IL-6, tumor-necrosis factor-α and other proinflammatory cytokines produced by the innate immune system stimulate immune activity and downregulate Tregs.6
IL-6 also abolishes the suppressive ability of Tregs in inflammatory conditions.7
Moreover, IL-6 enables natural Tregs to become Th17 cells that may assist the immune response in early inflammation.8,9
It has been shown that tumor cells produce large amounts of transforming growth factor-β, which has an essential role in converting Tnais to Tregs.10–13
In the late stages of inflammation, transforming growth factor-β becomes the predominant cytokine and subsequently promotes Treg differentiation and development.
In summary, the ratio of the three kinds of antigen components—antigens presented to Tregs, Teffs and Tnais—influences Tnai differentiation. The antigen non-specific interplay requires that the different antigens be presented closely—both temporally and spatially—to the T-cell subsets. This is seen when various APCs present different antigens in the same lymph node or when one APC captures many types of antigens.