Proliferative responses of circulating human NK cells: delineation of a unique pathway involving both direct and helper signals

Abstract

The present studies were performed to investigate mechanisms of human natural killer (NK) cell activation. NK-active cells were purified out of heterogeneous large granular lymphocytes (LGL)-enriched suspensions using a "pan NK"-specific monoclonal antibody termed anti-NKH1A. It was found that treatment of NKH1A+-sorted cells by T lymphocyte mitogens such as phytohemagglutinin (PHA) or anti-T11(2) plus anti-T11(3) did not induce proliferative responses. In fact, there was no measurable interleukin 2 (IL2) secretion and no significant increase in IL2 susceptibility following incubation with either PHA or anti-T11(2) plus anti-T11(3). However, as opposed to small resting T lymphocytes, NKH1A+ cells moderately proliferated in the presence of IL2. This IL2-dependent proliferation was dramatically increased after interaction between NK-active lymphocytes and certain hematopoietic cell lines such as K562 or EBV-transformed lymphoblastoid cell lines. These studies indicate that unique activation mechanisms can be identified when NK lymphocytes are purified out of LGL-enriched fractions. The NK activation pathway delineated here appears essentially distinct from those described for T lymphocytes. Indeed the nature of the NK cell/inducing cell interaction is unknown and triggering cannot be related, for example, to a conventional allogeneic effect mediated through membrane exposure of class I or class II major histocompatibility complex gene products. Moreover, these interactions do not lead to the development of autocrine responses. Together the present results support the view that direct signals can preactivate NK cells but are not sufficient to trigger proliferation which must therefore be regulated by helper populations.

The proteoglycan repertoire of lymphoid cells

“…However, the PHA-L induced increase in the synthesis and secretion of CS PG, presumably serglycin, was much higher in CD4+ and CD8+ T-cells than in NK- and B-cells. PHA-L is a mitogen which is known to stimulate T-cells, whereas NK-cells and B-cells are not reported to be significantly activated by PHA-L [36,37]. It was therefore not expected to be a large increase in expression of proteoglycan in these cells after PHA-L exposure.…”

Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes.

“…B lymphoblastoid cell lines also produce a variety of other lymphokines, including IL-1, IL-6, IFN-cx, IFN-(3, lymphotoxin (IT) 1 , and B cell growth factors (11)(12)(13)(14) . However, if soluble factors are involved in the effect of B cell lines, those factors are probably either active only at a short range or are produced only when the B cells are in contact with NK or T cells, since lymphocyte proliferation requires cell contact or at least contiguity (6,15) .…”

Decreased TcR‐CD3+ T cell numbers in healthy aged humans. Evidence that T cell defects are masked by a reciprocal increase of TcR‐CD3−CD2+ natural killer cells

“…2D, D66.1+ X11 CD2 mAb were not mitogenic for CD16'(CD3-) NK cells whereas CD3'(CD16-) T cells from the same donors were responsive. In summary, the phenotype and activation pathways of the TcR-CD3-CD2'16' population, expanded in the elderly, are different from those of thymus-derived lymphocytes but clearly similar to those of NK cells from young adults [13,17,181. Furthermore, the CD2'3-lymphocytes from the elderly share with NK cells from young adults their unresponsiveness to mitogens as well as a low cloning efficiency using limiting dilution procedures which allow cloning of the majority T cells (AlCs-Martinez, J. E., doctoral thesis).…”