An intense form of homeostatic proliferation of naive CD8+ cells driven by IL-2

Abstract

In conditions of T lymphopenia, interleukin (IL) 7 levels rise and, via T cell receptor for antigen–self–major histocompatibility complex (MHC) interaction, induce residual naive T cells to proliferate. This pattern of lymphopenia-induced “homeostatic” proliferation is typically quite slow and causes a gradual increase in total T cell numbers and differentiation into cells with features of memory cells. In contrast, we describe a novel form of homeostatic proliferation that occurs when naive T cells encounter raised levels of IL-2 and IL-15 in vivo. In this situation, CD8+ T cells undergo massive expansion and rapid differentiation into effector cells, thus closely resembling the T cell response to foreign antigens. However, the responses induced by IL-2/IL-15 are not seen in MHC-deficient hosts, implying that the responses are driven by self-ligands. Hence, homeostatic proliferation of naive T cells can be either slow or fast, with the quality of the response to self being dictated by the particular cytokine (IL-7 vs. IL-2/IL-15) concerned. The relevance of the data to the gradual transition of naive T cells into memory-phenotype (MP) cells with age is discussed.

The Role of Interleukin-2 in Memory CD8 Cell Differentiation

“…45 This combination leads to the formation of highly stimulatory IL-2/anti-IL-2 mAb complexes, which under in vivo conditions are able to stimulate polyclonal or TCR tg naïve CD8 + T-cells to differentiate into effector cells able to produce IFN-γ, tumor necrosis factor-α and granzyme B as well as lysis of target cells. 64,65 Subsequently, these IL-2/anti-IL-2 mAb complex-stimulated CD8 + cells differentiated into MP cells (for polyclonal cells) or central memory cells (in the case of TCR tg cells). For TCR tg cells, OT-I memory CD8 + cells generated by activation with IL-2/anti-IL-2 mAb complexes in the absence of antigen conferred efficient protection against challenge with recombinant LM expressing ovalbumin.…”

“…Such proliferation occurs when naïve CD8 + cells are transferred to CD25 -/-or CD122 -/-mice; not being able to utilize IL-2, these mice have high levels of IL-2 and also IL-15 in the case of CD122 -/-mice. 64 Antigen-independent proliferation of naïve CD8 + cells to IL-2 also occurs after administration of rIL-2 mixed with a particular anti-IL-2 monoclonal antibody (mAb). 45 This combination leads to the formation of highly stimulatory IL-2/anti-IL-2 mAb complexes, which under in vivo conditions are able to stimulate polyclonal or TCR tg naïve CD8 + T-cells to differentiate into effector cells able to produce IFN-γ, tumor necrosis factor-α and granzyme B as well as lysis of target cells.…”

MHC-dependent desensitization of intrinsic anti-self reactivity

“…competition for the cytokine interleukin-7 (IL-7) seems to be a major driving force for HP, although recent data suggest that HP may occur under more specialized conditions associated with increased concentrations of IL-2 and IL-15 [1][2][3][4]. The control of HP is multifactorial and often favors memory T cells over naïve T cells; for example, clonal competition promotes expansion of memory cells at the expense of naïve cells [5;6], cytokine responsiveness similarly tilts the composition of the reconstituted population towards cells with memory phenotypes (MP) [7], and regulatory (CD4/CD25/FoxP3+) T cells (Treg) also can contribute to the balance of naïve and memory cells that repopulate a lymphopenic environment [8].…”

“…Specifically, the tempo of IL-7 mediated HP is slow [9], HP driven by constitutive levels of IL-15 is more rapid, generating memory phenotype cells [4], and HP driven by elevated levels of IL-2/IL-15 is rapid with differentiation into both effector and memory phenotype cells [2]. While the slow paced (IL-7-dependent) HP seems to be restrained by signals delivered through CD24 expressed in bone marrow derived dendritic cells (DC) [10], differentiation from naïve T cells to MP T cells following rapid IL-2 and IL-15 dependent HP is comparable to events driven by encounter with foreign antigen.…”

“…Experiments using transgenic T cells show that HP applies to most TCR transgenic animals, although the intensity of proliferation varies from one TCR transgenic line to another [2]. The especially weak proliferation of HY transgenic T cells may reflect the observation that they have below average affinity for self-peptide/MHC and/or low TCR promiscuity [29;30].…”