What are Null Cells?

Null cells are also called as third population cells. Small fractions (-2%) of the lymphocytes circulating in the blood are neither T cells nor B cells.

Most of these are called natural killer (NK) cells because they are specialized to kill certain types of target cells, especially host cells that are infected with virus or modified to tumor cells. Unlike T and B cells, null cells lack immunologic memory and specificity.

The specificity of the receptors with which NK cells recognize potential targets are not diversified like the T and B cells. Comparatively null cells are large in size with large granules of performing and granzymes in their cytoplasm. They produce a number of immunologically important cytokines and play regulatory role in both cell mediated and humoral immune response.

Stromal cell secretions in the surroundings of null cells play a vital role in their maturation. NK cells contain “activating receptors” and “Killer Inhibitory Receptors” (KIRs). When an NK cell binds to a target cell without class I MHC molecules, the activating receptors trigger the killing activity in NK cell. Killer inhibitory receptors (KIRs) convey an inhibitory signal to the NK cells if they encounter class I MHC molecules on target cell surface.

Since viruses often suppress the expression of class I MHC in host cells, the virus-infected cells happen to be susceptible for NK cells killing activity. In the same way, cancer cells showing reduced or no class I MHC expression are vulnerable to killing by NK cells.

Lineage of NK cells is not clearly understood, however genes for NK receptors illustrate polymorphism. Hence the variety of NK receptors differs from person to person.

Research information in this field has shown that IL-15 (interleukin -15) potentially promotes NK cells development from NK precursors (NKPs) and IL- 2 could maintain NK cell’s survival and drive their development from committed precursors.

Hence IL- 2 and IL -15 are vital for NK cell generation. Absence of IL – 15 signaling cause severe reduction in the number of NK cells. Even though they possess certain T lymphocyte markers they are independent of MHC molecules to execute their lyric function on target cells. Because of this character NK cells provide first line of defense. When NK cells adhere to the target cell, they release perforin and granzymes at the junction of their interaction. The perforin causes pore formation on the target cell that results in its death through leakage of its contents and the granzymes induce apoptosis of the target cell.

Since NK cells are preprogrammed to recognize their targets, they are able to respond rapidly, thus providing an important tool in innate immunity. In addition to killing target cells, NK cells secrete cytokines such as anti-viral cytokine IFN-y and inflammatory cytokine TNF-a.

Since surface receptors of different null cells are different, their functions also vary.

Based on functions null cells can be broadly divided in to two groups (a) Natural Killer cells, (b) Killer cells.

(a) Natural killer cells or NK cells:

They are about 15pm in diameter with a kidney shaped nucleus and azurophilic granules in their cytoplasm. NK cells are morphologically distinguishable from the other lymphocytes through the presence of 2 or 3 large granules in their cytoplasm. They exhibit spontaneous killer activity against any foreign cells, tumor cells, pathogen infested auto cells etc., even in the absence of prior stimulation.

Therefore NK cells represent first line of defense to infections, tumor growth and other pathogenic alterations in tissue homoeostasis. NK cells are non phagocytic and non adherent to surfaces, but release perforin in close proximity to a cell selected for killing. Perforin forms pores in the cell membrane of the target cell through which the granzymes and associated molecules can enter inducing apoptosis.

Granzymes are serine proteases that are released by cytoplasmic granules within cytotoxic T cells and natural killer cells.

Granzyme B (GrB) and perforin were found to coexist as multimeric complexes with the proteoglycan serglycin (SG) in cytotoxic granules, and cytotoxic cells were observed to secrete exclusively macromolecular GrB-SG. Their purpose is to induce apoptosis within virus- infected cells, thus destroying them.

Since they are capable of identifying alterations in surface markers of the auto cells, NK cells provide natural toxicity. Different surface receptors for activation and inhibitory signals are identified but the exact regulatory mechanism of NK cells is not yet clearly understood.

Even though all NK cells are equally efficient in cytolytic activity, the mode of activation is different. Certain sub sets of NK populations show priority in killing tumor cells and others kill virus or bacteria infected cells.

Irrespective of their killing priority they do not require any support from T cells or antigen presenting cells for their function or activation.

Azurophil is the term used to refer to objects that are readily staining with an azure dye. The term is used especially in reference to certain cytoplasmic granules in white blood cells, particularly hyperchromatin and reddish purple granules of certain blood cells.

(b) Killer Cells (or) K Cells:

K cells are antibody dependent for their activity. Due to this character K cells are also referred as antibody dependent cytotoxic cells (ADCCs). They possess receptors for Fc region of antibody; binding of antibody through Fc region to these receptors induces release of cytotoxic substances such as perforin, granzymes etc., in close proximity of antibody bound target cell.

The released cytotoxic substances are responsible for lysis of target cell. Compliment fixation is not required for the lytic action of K cells. Like T cells, K cells can react with sheep erythrocytes and form rosettes.