Natural Killing and Adaptive Immunity: the role of NK cells in CD8+ T cell differentiation

In the human immune response, an encounter with a pathogen results in the rapid division of immune cells which neutralize and kill viruses, bacteria and parasites. While this rapid increase in the number of immune cells in the body is necessary for a robust and effective immune response, once the pathogen has been cleared it is essential that immune cell levels be brought back down to normal. CD8⁺ T cells, also known as cytotoxic T lymphocytes (CTLs), are one type of immune cell that follows this pattern of expansion and contraction. In the presence of an antigen, CD8⁺ T cells specific for that antigen divide rapidly, seeking out and killing infected cells and pathogens. When the threat has been cleared, high levels of CD8⁺ T cells specific for a single antigen are no longer necessary, and the majority of CD8⁺ T cells die by apoptosis. The surviving CD8⁺ T cells differentiate into memory T cells, allowing the body to respond more quickly and effectively the next time it encounters the same antigen. This process is essential for maintaining immunity to diseases; the memory T cells and B cells produced after an initial exposure are the reason that, for example, you only get chicken pox once. Similarly, memory T cells and B cells enable the body to prevent infection by pathogens against which it has been vaccinated.

In a paper published in the Journal of Immunology just this week, Soderquest, et al. examine the relationship between CD8+ s and natural killer cells (NK cells) after an infection has been cleared. NK cells are an important part of innate immunity – that is, the rapid and general immune response that includes both physical barriers to infection (i.e. the skin and mucosa) and non-specific killing cells like the NK cell. During the innate immune response, NK cells identify and kill cells that are either infected with viruses or are tumorigenic. Apart from their role in the innate immune response, recent studies have shown that NK cells play an important part in the development of the more specific adaptive immune response, particularly in promoting the differentiation of CD4⁺ “helper” T cells (Th cells). In investigating the relationship between CD8⁺ T cells and NK cells, Soderquest et al. focused on the NKG2D pathway of NK cell killing. NKG2D is a protein expressed on the surface of NK cells that binds to NKG2D ligand (NKG2DL) on a target cell and induces apoptosis via the perforin/granzyme pathway. The authors of this article hypothesized that NK cells influence the development of CD8⁺ T cell-mediated adaptive immunity by killing activated CD8⁺ T cells via the NKG2D/perforin pathway.

In order to test this hypothesis, the authors first examined the production of CD8⁺ T cells in both the presence and absence of NK cells. In a mouse model, the authors “primed” CD8⁺ T cells with an antigen and measured the number of CD8⁺ T cells present in the blood serum after six days. In mice with no NK cells, the number of CD8⁺ T cell was significantly higher than in those expressing a normal population of NK cells. These results strongly suggested that NK cells were playing some role in reducing the number of CD8⁺ T cells after exposure to an antigen. To better understand the effects of NK cell absence on CD8⁺ T cell development, Soderquest et al. compared the phenotypes of CD8⁺ T cells differentiating in the presence or absence of NK cells. Interestingly, the authors found that the presence of NK cells significantly affected what proteins were expressed on the surface of differentiating CD8⁺ T cells: the absence of NK cells resulted in a dramatic upregulation of surface proteins CD26L and CCR7.

Having determined that the presence of NK cells was associated with both a decrease in the number of activated CD8⁺ T cells and a significant change in their expression of surface proteins, the authors attempted to identify the method by which NK cells were reducing the CD8⁺ T cell population. Previous research had found that, within 24-48 hours of exposure to an antigen, CD8⁺ T cells began to express NKG2DL on their membranes. To confirm that CD8⁺ T cells were being killed by NKG2D/NKG2DL interaction, the authors activated CD8⁺ T cells in two groups of mice whose NK cells expressed and did not express NKG2D, respectively. The authors found that in mice whose NK cells did not express NKG2D, the population of activated CD8­_­⁺ T cells was nearly identical in size to that of mice that did not have any NK cells. These results suggest that NK cells kill activated CD8⁺ T cells via the NKG2D/perforin pathway.

Finally, the researchers examined the effect of NK cells on the fate of activated CD8⁺ T cells that survived NKG2D/perforin-mediated killing. Soderquest, et al found that, in the absence of NK cells, activated CD8⁺ T cells tended to produce central memory T cells (T_CM), whereas in the presence of NK cells, memory cell production was skewed toward effector memory T cells (T_EM). Since T_CM cells had previously been implicated in improved antitumor immunity, the authors then tested whether mice whose CD8⁺ T cells had differentiated in the absence of NK cells were better able to resist tumor growth. After a 21 day trial, in which both subsets of mice were inoculated with tumorigenic tissue, the mice with the larger population of T_CM cells displayed markedly slower tumor growth than their T_EM counterparts.

This research is a step forward in understanding the complex, interrelated nature of innate and adaptive immunity. Whereas the role of NK cells as effectors was once thought to be limited to antiviral and tumor-suppressant cell killing, it is now clear that the presence of NK cells has a profound effect on the differentiation of both CD4⁺ and CD8⁺ T cells. Perhaps the most striking finding of this paper is the dramatic increase in the production of T_CM­ cells in the absence of NK cells. In mice, T_CM cells have been shown to provide a more robust response to subsequent antigen exposure than their T­­_EM counterparts, conferring greater protection against bacteria, viruses and cancerous cells . The identification of NKG2D- and perforin-mediated killing as a factor in CD8+ memory cell differentiation holds interesting implications for future immune research. With a greater understanding of how the body skews CD8+ T cell differentiation away from the more effective memory cell, future research may attempt to reverse this tendency, providing a boost to adaptive immunity against tumors and pathogenic infection.

Primary Article:

Soderquest, K., Walzer, T., Zafirova, B., et al. 2011. Cutting Edge: CD8⁺ T Cell Priming in the Absence of NK Cells Leads to Enhanced Memory Responses. J. Immunol.: 186: 3304-3308.

Additional Sources:

Martin-Fontecha, A., L. L. Thomsen, S. Brett, C. Gerard, M. Lipp, A. Lanzavecchia, and F. Sallusto. 2004. Induced recruitment of NK cells to lymph nodes provides IFNgamma for T(H)1 priming. Nat. Immunol. 5: 1260–1265.

Raulet, D. H. 2003. Roles of the NKG2D immunoreceptor and its ligands. Nat. Rev. Immunol. 3: 781–790.

Klebanoff, C. A., L. Gattinoni, P. Torabi-Parizi, K. Kerstann, A. R. Cardones, S. E. Finkelstein, D. C. Palmer, P. A. Antony, S. T. Hwang, S. A. Rosenberg, et al. 2005. Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc. Natl. Acad. Sci. USA 102: 9571–9576.