Components of the innate immune system generally respond to pathogens by either recognizing common features (known as pathogen-associated molecular patterns, or PAMPs) or via receptors that scan for signs of distress on infected cells (such as the absence of cell surface molecules called MHC class I receptors, which are essentially immunological alarm bells that some pathogens nefariously disable). Recently, it has been shown that innate immunity can sometimes be mobilized to mount a more specific response to individual pathogens than was once thought possible.
As covered in a previous post, Louise Kuhn’s research group has discovered evidence that natural killer (NK) cells recognize and retain memory of HIV peptides, and these NK responses may play a role in preventing mother-to-child HIV transmission. In a new paper in the Journal of Infectious Diseases, the same group of researchers reports that NK cell recognition of HIV peptides is also associated with lower HIV viral loads and higher CD4 counts in the a cohort of 79 HIV‐infected, postpartum women. In addition, the study found that the magnitude of the NK cell response was linked to the number of CD4 T cells targeting the HIV Gag protein, and the authors state that: “These findings can be interpreted in the following ways: (1) in vivo CD4 Gag responses may provide help for HIV‐specific NK cells, (2) HIV‐specific NK cells provide help to maintain and preserve CD4 T cell responses, or (3) NK‐CD4 T cell responses help each other in a bidirectional fashion. All these possibilities may in turn also lead to better quality CD8 T cell responses.”
Two recent basic immunology papers offer further evidence of linkages between specific, adaptive immune responses by CD4 T cells and innate immunity. In one case, memory CD4 T cells targeting rabies are shown to mobilize natural killer cells upon secondary exposure to the virus. The authors conclude that induction of NK cell responses may be an under-appreciated mechanism by which vaccine-induced memory CD4 T cells mediate protective immunity. These findings may even deserve consideration in the context of the Thai prime-boost HIV vaccine trial, as memory CD4 T cell responses were induced against HIV Gag p24 in around 50% of recipients in a small (n=71) immunogenicity analysis. The second paper, from Susan Swain’s research group at the Trudeau Institute, reports that memory CD4 T cells can induce production of multiple innate inflammatory cytokines and chemokines in the lung, and that this is associated with earlier control of influenza virus infection. Taken together, the results of these studies suggest that the ability of vaccine-induced memory T cell responses to recruit innate immunity should be specifically evaluated in future research.
The Journal of Infectious Diseases 2010;202:000–000
Caroline T. Tiemessen,1 Sharon Shalekoff,1 Stephen Meddows‐Taylor,1 Diana B. Schramm,1 Maria A Papathanasopoulos,2 Glenda E. Gray,5 Gayle G. Sherman,2,4 Ashraf H. Coovadia,3 and Louise Kuhn6
1AIDS Virus Research Unit, National Institute for Communicable Diseases and Department of Virology, 2Department of Molecular Medicine and Haematology, and 3Empilweni Clinic, Coronation Women and Children Hospital, Enhancing Childhood HIV Outcomes, University of the Witwatersrand, and 4National Health Laboratory Services, Johannesburg, and 5Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, Soweto, South Africa; and 7Gertrude H. Sergievsky Centre, College of Physicians and Surgeons and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York
Human immunodeficiency virus (HIV)–specific natural killer (CD3− cells), CD4, and CD8 T cellular responses were determined in 79 HIV‐1–infected women in response to HIV‐1 peptide pools (Gag, Pol, Nef, Reg, and Env) with use of a whole‐blood intracellular cytokine staining assay that measures interferon–γ and/or interleukin–2. HIV‐specific CD3− cell responses to any region (Env and Reg predominantly targeted) were associated with lower viral load (P=.031) and higher CD4 T cell count (P=.015). Env‐specific CD3− cell responses were stronger in women who had both Gag CD4 and CD8 T cell responses and, in turn, was associated with lower viral load (P=.005). CD3− cell responders had significantly higher representation of CD4 T cell responses to Env and Reg (P=.012 and P=.015, respectively) and higher magnitudes of CD4 T cell responses (P=.017 and P=.037, respectively) than did nonresponders. Peptide‐specific natural killer cells are associated with markers of less severe disease progression among HIV‐1–infected women (lower viral load and higher CD4 T cell count) and with stronger HIV‐specific T cell responses.
The Journal of Immunology, 2010, 185, 2808 -2818
Amir Horowitz,* Ron H. Behrens,*, Lucy Okell,* Anthony R. Fooks, and Eleanor M. Riley*
*Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine; Department of Travel Medicine, Hospital for Tropical Diseases, London; and Rabies and Wildlife Zoonoses Group, World Health Organization Collaborating Centre of Rabies and Rabies-Related Viruses, Veterinary Laboratories Agency, Surrey, United Kingdom
We characterized vaccine-induced cellular responses to rabies virus in naive adult volunteers. Contrary to current paradigms, we observed potent and prolonged in vitro NK cell cytokine production and degranulation responses after restimulation of PBMCs with inactivated rabies virus in vaccinated, but not in unvaccinated, individuals. This "recall" NK cell response was absolutely dependent on Ag-specific IL-2 from CD45RO+ CD4+ T cells as well as IL-12 and IL-18 from accessory cells. Importantly, NK cells represented over 70% of all IFN-–secreting and degranulating cells in the first 12–18 h after virus rechallenge indicating they may be required for rapid control of infection after vaccination. Activation of NK cells may be a critical function of IL-2–secreting effector memory T cells. Although IL-2–dependent postvaccination NK cell activation has been reported previously, this is the first time the magnitude of this effect and its contribution to the overall vaccine-induced response has been appreciated and the mechanisms of NK activation postvaccination have been elucidated. Our data will allow standard protocols for evaluating vaccine-induced immunity to be adapted to assess NK cell effector responses.
Nat Med. 2010 May;16(5):558-64, 1p following 564. Epub 2010 May 2.
Strutt TM, McKinstry KK, Dibble JP, Winchell C, Kuang Y, Curtis JD, Huston G, Dutton RW, Swain SL.
Trudeau Institute, Saranac Lake, New York, USA.
Inflammation induced by recognition of pathogen-associated molecular patterns markedly affects subsequent adaptive responses. We asked whether the adaptive immune system can also affect the character and magnitude of innate inflammatory responses. We found that the response of memory, but not naive, CD4(+) T cells enhances production of multiple innate inflammatory cytokines and chemokines (IICs) in the lung and that, during influenza infection, this leads to early control of virus. Memory CD4(+) T cell-induced IICs and viral control require cognate antigen recognition and are optimal when memory cells are either T helper type 1 (T(H)1) or T(H)17 polarized but are independent of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) production and do not require activation of conserved pathogen recognition pathways. This represents a previously undescribed mechanism by which memory CD4(+) T cells induce an early innate response that enhances immune protection against pathogens.