Control Of Effector Functions Research Articles

Modulation of T-bet and Eomes during Maturation of Peripheral Blood NK Cells Does Not Depend on Licensing/Educating KIR.

Peripheral natural killer (NK) cells upregulate T-bet and downregulate Eomes, the key transcription factors regulating NK cell maturation and function during the last maturation steps toward terminally differentiated effector cells. During this process, NK cells acquire killer immunoglobulin-like receptors (KIR) and effector functions, such as cytotoxicity and target cell-induced cytokine production. Inhibitory KIR are pivotal in the control of effector functions, but whether they also modulate T-bet/Eomes expression is unknown. We have measured T-bet/Eomes levels, KIR expression, and effector functions of maturing CD94negCD56dimNK cells using CD57 as surface marker for maturation. Our cohort consisted of 23 healthy blood donors (HBD) homozygous for the KIR A haplotype that contains only inhibitory KIR2DL1 (ligand HLA-C2), KIR2DL3 (ligand HLA-C1), and KIR3DL1 (ligand HLA-Bw4). We confirm that during maturation of NK cells, the number of KIR increases, levels of T-bet/Eomes are modulated, and that cells acquire effector functions, such as cytotoxicity (CD107) and target cell-induced cytokine production (TNF-α). Because maturation was associated with the increase of the number of KIR as well as with the modulation of T-bet/Eomes, the number of KIR correlated with the extent of T-bet/Eomes modulation. However, whether the KIR were triggered by their cognate HLA ligands or not had no impact on T-bet and Eomes expression, indicating that modulation of T-box transcription factors during NK cell maturation does not depend on signals conveyed by KIR. We discuss the relevance of this finding in the context of models of NK cell maturation while cautioning that results obtained in a perhaps quite heterogeneous cohort of HBD are not necessarily conclusive.

Control of Cytotoxic Lymphocyte Survival in Vivo By Members of the TNF-R Family.

Cytotoxic lymphocytes expressing perforin and granzymes are important effectors for the clearance of viral infections, for immune surveillance and rejection of tumors. They also participate in allogeneic transplant rejection and graft versus host disease. The emergence and survival of cytotoxic CD8+ T lymphocytes (CTL), an important subpopulation among cytotoxic lymphocytes, is carefully regulated both at the level of their generation and their removal. The process is further controlled by the fact that CTL are generated in draining lymph nodes but must exert their effector function at distant sites in tissues (1). Control of effector function therefore must be carefully integrated with CTL migration and apoptosis. Dramatic expansion of CTL from their precursors can be achieved by secreted heat shock protein gp96-Ig (2) that is recognized by CD91 on dendritic cells, potent antigen presenting cells for T cells. Heat shock protein vaccines cause clonal expansion of cognate TCR transgenic preCTL from a frequency of 20% of the CD8 pool within one week and, upon boosting the response, to >50% of all CD8 cells. This system offers an ideal setting for assessing the homeostatic control of effector CTL pools in vivo and measuring their effector cell activity. Activated CD8+ CTL express numerous receptors and ligands of the TNF-R family. The role of Fas and Fas-L in T cell survival is well documented. Deficiency of either receptor or ligand results in lymphoproliferative disease and autoimmunity, demonstrating a significant function for Fas and Fas-L in terminating clonal expansion and triggering cell removal. CD8+ CTL of the memory phenotype (CD45RO) upon activation transiently expresses very high levels of CD30, another member of the TNF-R family (3), suggesting an important role for this molecule on CTL. While CD30 is not endowed with a death domain, it can nonetheless signal to FADD via its TRAF binding ability. On the other hand CD30 signals are also able to activate NF-kB and JUNK resulting in proliferation. Recent studies suggest that CD30 signals elicited on cytotoxic lymphocytes may integrate effector function (cytotoxicity), lymphocyte migration and susceptibility to apoptosis. Signals emanating from CD30 up regulated CCR7, down regulated the cytotoxic molecules perforin and granzyme B and affected both pro- and anti-apoptotic molecules. One interpretation of these data suggests that CD30-L expressed in tissues may down regulate effector cell cytotoxicity and redirect CTL towards lymph nodes via the CCR7 receptor (4). Recirculation of CTL to lymph nodes allows reactivation or reprogramming of the effector response, including initiation of apoptosis.