Neutrophils Influence the Magnitude and Spread of Immune Responses to Protein Antigens by a Prostaglandin Mediated Process

We have studied the influence of neutrophils on the immune responses to protein antigens in adjuvants. Neutrophils enter lymph nodes shortly after immunization starting during the first hour and continuing for several days. We demonstrated the suppressive effects of neutrophils on CD4 T cell as well as Ab responses by using neutrophil depleting Abs or genetically neutropenic mice. One of the mechanisms by which neutrophils modulated the extent of T cell responses was by reducing the amount of antigen available to the APC. Neutrophil-DC interaction also affected the interaction of DC with T cells. We also found that neutrophils control the spread of T cell responses to distant lymph nodes. In the presence of neutrophils about 75% of the response is restricted to the draining node but in their absence most of the response is found in distal nodes. A critical component of the control of the spread in the response is the production of prostaglandins, a great part made by the entering neutrophils. Prostaglandin deficient mice or in vivo inhibition of prostaglandin production by indomethacin in the presence of neutrophil entry showed unrestricted response similar to that found in neutropenic mice. Adoptive transfer of neutrophils treated with indomethacin or transferring neutrophils from prostaglandin deficient mice into genetically neutropenic recipients supported a role for neutrophil-expressed prostaglandins in restricting T cell responses in popliteal nodes. By quantitative RT-PCR, activated neutrophils transcribed Ptgs-1 and Ptgs-2, genes for cycloxygenase-1 and -2. Mass spectrometry demonstrated high levels of prostaglandin production from neutrophils. In brief neutrophils modulate the extent of the T cell response and also the spread of T cell responses in a prostaglandin mediated process