TCR‐independent cytokine stimulation induces non‐MHC‐restricted T cell activity and is negatively regulated by HLA class I

Abstract

Recent evidence suggests that the functional status of T cells activated independently from their TCR differs substantially from classical MHC-restricted T cells. Here, we show that TCR-independent, short-term stimulation via the common c-chain of the IL-2/IL-15 receptor induces non-MHC-restricted cytotoxicity and sustained cytokine secretion in purified CD4 + or CD8 + T cells. NK-like cytotoxicity is directed against MHC class Inegative targets and can be inhibited by classical and non-classical HLA class I molecules. Known inhibitory receptors, such as CD85j (ILT2) and leukocyte-associated Ig-like receptor-1, are not responsible for this HLA-mediated inhibition. NK-like cytotoxicity can be costimulated by NKG2D (CD314) triggering, but 2B4 (CD244) and DNAM-1 (CD226) are not involved. NK-like T cells display an activated phenotype and secrete various cytokines, including IFN-c, TNF-a, IL-5, IL-13 and MIP-1b. Under normal conditions, HLA class I-mediated inhibition may function as a safety mechanism to prevent unbalanced cytokine production and effector killing mechanisms by T cells that were activated independently from their TCR. Non-MHC-restricted activity represents a functional status rather than a property of distinct T cell subpopulations. Thus, cytokine-induced, non-MHC-restricted T cells may be relevant in immune responses against tumors showing aberrant MHC expression through their capacities of cytokine production and direct tumor cell eradication.

Natural Killer Cells are Scarce in Colorectal Carcinoma Tissue Despite High Levels of Chemokines and Cytokines

“…Our results, therefore, could be interpreted in different aspects: lesions (and cannot be compared to the primary tumor) and this has to be taken into account when designing interventional trials. In detail, the comparison of the NKspecific marker NKp46 with CD56 revealed that NK-cell quantities cannot be estimated from staining with CD56 alone (19)(20)(21). For other gastrointestinal cancers, the available data is ambiguous due to the use of CD56 in stainings.…”

Human CD4+ Memory T Cells Are Preferential Targets for Bystander Activation and Apoptosis

“…There are two chief schools of thought: bystander T cell activation results in effector functions (5,7,12,13,48), which may be damaging (in the case of immunopathology) or helpful (contributing to resolution of infection (49 -52)); alternatively, bystander T cell activation simply results in apoptosis and attrition of the existing repertoire to make way for the newly expanded, directly activated T cells. There is considerable evidence that bystander T cells undergo attrition.…”

“…There is much evidence that cytokine stimulation (5)(6)(7)(8)(9)(10)(11)(12)(13) or cross-linking of certain membrane-bound receptors (14,15) is capable of activating T cells in the absence of TCR ligation. Few studies, however, address whether physiological levels of these cytokines produced during an immune response do actually induce bystander T cell activation.…”

Downregulation of CD4+CD25+ regulatory T cells may underlie enhanced Th1 immunity caused by immunization with activated autologous T cells

“…CD62L is usually expressed at a high level on resting T cells [36,37], while CD25, the α-chain of IL-2 receptor expressed upon T-cell activation, has been used as a marker for activated T cells [38][39][40]. The data showed CD62L+ Tcell population was reduced (and thus CD62L low population was increased) in PBMC from immunized mice.…”