Perforin deficiency: fighting unarmed?

In the June issue of Immunology Today, Stepp and colleagues1xPerforin: more than just an effector molecule. Stepp, S.E. et al. Immunol. Today. 2000; 21: 254–256Abstract | Full Text | Full Text PDF | PubMed | Scopus (96)See all References1 reviewed the growing evidence that perforin, a cytotoxic protein that lymphocytes secrete to kill virus-infected cells, also controls lymphocyte proliferation2.xPerforin gene defects in familial hemophagocytic lymphohistiocytosis. Stepp, S.E. et al. Science. 1999; 286: 1957–1959Crossref | PubMed | Scopus (730)See all References, 3.xA role for perforin in downregulating T-cell responses during chronic viral infection. Matloubian, M. et al. J. Virol. 1999; 73: 2527–2536PubMedSee all References, 4.xA role for perforin in activation-induced T cell death in vivo: increased expansion of allogeneic perforin-deficient T cells in SCID mice. Spanner, D. et al. J. Immunol. 1999; 162: 1192–1199See all References, 5.xHomeostatic regulation of CD8+ T cells by perforin. Kagi, D. et al. Eur. J. Immunol. 1999; 29: 3262–3272Crossref | Scopus (124)See all References. This exciting idea follows from the recent findings that familial hemophagocytic lymphohistiocytosis (FHL), a fatal lymphoproliferative disorder triggered by viral infection in humans, results from a perforin defect2xPerforin gene defects in familial hemophagocytic lymphohistiocytosis. Stepp, S.E. et al. Science. 1999; 286: 1957–1959Crossref | PubMed | Scopus (730)See all References2; and that perforin-deficient mice exhibit a similar lymphoproliferative disorder following viral infection3xA role for perforin in downregulating T-cell responses during chronic viral infection. Matloubian, M. et al. J. Virol. 1999; 73: 2527–2536PubMedSee all References3. The authors suggested that perforin could trigger lymphocyte apoptosis, or repress proliferative signals, through as-yet unknown pathways. But given the evidence2.xPerforin gene defects in familial hemophagocytic lymphohistiocytosis. Stepp, S.E. et al. Science. 1999; 286: 1957–1959Crossref | PubMed | Scopus (730)See all References, 3.xA role for perforin in downregulating T-cell responses during chronic viral infection. Matloubian, M. et al. J. Virol. 1999; 73: 2527–2536PubMedSee all References, 4.xA role for perforin in activation-induced T cell death in vivo: increased expansion of allogeneic perforin-deficient T cells in SCID mice. Spanner, D. et al. J. Immunol. 1999; 162: 1192–1199See all References, 5.xHomeostatic regulation of CD8+ T cells by perforin. Kagi, D. et al. Eur. J. Immunol. 1999; 29: 3262–3272Crossref | Scopus (124)See all References, could regulation instead be a consequence of perforin's accepted role in killing infected cells?Mathematical modeling suggests that it could (Fig. 1Fig. 1). Consider viral infection in an otherwise healthy person. Infection triggers a normal immune response, marked by lymphoproliferation and perforin-mediated killing of infected cells6xCytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Kagi, D. et al. Nature. 1994; 369: 31–37Crossref | PubMed | Scopus (1275)See all References6. The death of infected cells removes the stimulus for further proliferation, allowing the number of lymphocytes to return to normal7.xHomeostasis and self-tolerance in the immune system: turning lymphocytes off. Van Parijs, L. and Abbas, A.K. Science. 1998; 280: 243–248Crossref | PubMed | Scopus (753)See all References, 8.xImmunological memory and protective immunity: understanding their relation. Ahmed, R. and Gray, D. Science. 1996; 272: 54–60Crossref | PubMedSee all References, 9.xPopulation dynamics of immune responses to persistent viruses. Nowak, M.A. and Bangham, C.R. Science. 1996; 272: 74–79Crossref | PubMedSee all References. Contrast this with the case for a person with a perforin defect. Infection still triggers lymphoproliferation. But without perforin, lymphocytes are unable to control infection. Hence the stimulus for proliferation remains, lymphoproliferation continues, and the result is lymphoproliferative disease. In this scenario, lymphoproliferation is simply the body's attempt to compensate for its difficulty in controlling infection. The lymphocytes are like soldiers at war: the worse they are armed, the more that are needed, and the more that are sent in (Fig. 1Fig. 1).Fig. 1Perforin regulation by dynamic compensation. Consider two populations: infected cells (y) and the lymphocytes that respond to and kill them (z). The relationship between the two can be described by predator–prey dynamics according to a system of differential equations derived from the standard model of virus dynamics9xPopulation dynamics of immune responses to persistent viruses. Nowak, M.A. and Bangham, C.R. Science. 1996; 272: 74–79Crossref | PubMedSee all References9: dy/dt=βy−pyz and dz/dt=cyz−bz. Infection spreads at an average rate βy; lymphocytes respond to infection at an average rate cyz, die at an average rate bz, and control infection at an average rate pyz. This model converges to an equilibrium where infected cell and lymphocyte frequencies are given by y*=b/c and z*=β/p, respectively. These expressions are consistent with findings of similar viral loads in wild-type and perforin-deficient mice3xA role for perforin in downregulating T-cell responses during chronic viral infection. Matloubian, M. et al. J. Virol. 1999; 73: 2527–2536PubMedSee all References3. Because perforin is cytolytic, a perforin defect corresponds to a decrease in p. Since p and z* vary inversely, a loss of perforin therefore results in an increased number of lymphocytes. For example, suppose a perforin defect such as that in FHL robs lymphocytes of 99% of their function (pFHL=0.01phealthy). The model predicts that FHL individuals would then exhibit a 100-fold increase in lymphocyte frequency compared with healthy individuals. Note that a host may die from the effects of uncontrolled lymphoproliferation before equilibrium is reached. Model parameters were β=c=b=1.0. A value of p=1.0 corresponds to healthy lymphocyte function; p=0.0 corresponds to lymphocytes that are completely nonfunctional.View Large Image | Download PowerPoint SlideThis ‘dynamic compensation’ theory is appealing because it explains the salient findings2.xPerforin gene defects in familial hemophagocytic lymphohistiocytosis. Stepp, S.E. et al. Science. 1999; 286: 1957–1959Crossref | PubMed | Scopus (730)See all References, 3.xA role for perforin in downregulating T-cell responses during chronic viral infection. Matloubian, M. et al. J. Virol. 1999; 73: 2527–2536PubMedSee all References, 4.xA role for perforin in activation-induced T cell death in vivo: increased expansion of allogeneic perforin-deficient T cells in SCID mice. Spanner, D. et al. J. Immunol. 1999; 162: 1192–1199See all References, 5.xHomeostatic regulation of CD8+ T cells by perforin. Kagi, D. et al. Eur. J. Immunol. 1999; 29: 3262–3272Crossref | Scopus (124)See all References without having to invoke new roles for perforin. It will be interesting to see whether further investigation will bear it out.