TIM-4, expressed by medullary macrophages, regulates respiratory tolerance by mediating phagocytosis of antigen-specific T cells.

Respiratory exposure to antigen induces T cell tolerance via several overlapping mechanisms that limit the immune response. While the mechanisms involved in the development of Treg cells have received much attention, those that result in T cell deletion are largely unknown. Herein, we show that F4/80(+) lymph node medullary macrophages expressing TIM-4, a phosphatidylserine receptor, remove antigen-specific T cells during respiratory tolerance, thereby reducing secondary T cell responses. Blockade of TIM-4 inhibited the phagocytosis of antigen-specific T cells by TIM-4 expressing lymph node medullary macrophages, resulting in an increase in the number of antigen-specific T cells and the abrogation of respiratory tolerance. Moreover, specific depletion of medullary macrophages inhibited the induction of respiratory tolerance, highlighting the key role of TIM-4 and medullary macrophages in tolerance. Therefore, TIM-4-mediated clearance of antigen specific T cells represents an important previously unrecognized mechanism regulating respiratory tolerance.

Changes in antigen-specific T-cell number and function during oral desensitization in cow's milk allergy enabled with omalizumab.

Food allergy is a major public health problem, for which there is no effective treatment. We examined the immunological changes that occurred in a group of children with significant cow's milk allergy undergoing a novel and rapid high-dose oral desensitization protocol enabled by treatment with omalizumab (anti-immunoglobulin (Ig)E monoclonal antibodies). Within a week of treatment, the CD4(+) T-cell response to milk was nearly eliminated, suggesting anergy in, or deletion of, milk-specific CD4(+) T cells. Over the following 3 months while the subjects remained on high doses of daily oral milk, the CD4(+) T-cell response returned, characterized by a shift from interleukin-4 to interferon-γ production. Desensitization was also associated with reduction in milk-specific IgE and a 15-fold increase in milk-specific IgG4. These studies suggest that high-dose oral allergen desensitization may be associated with deletion of allergen-specific T cells, without the apparent development of allergen-specific Foxp3(+) regulatory T cells.

Validation of a portable equine metabolic measurement system.

REASONS FOR PERFORMING STUDY: In equine sports medicine, VO2 has been measured exclusively with stationary systems, in laboratories equipped with a treadmill. Measurement during exercise in field conditions has not previously been reported because of the lack of portable equipment designed for horses. OBJECTIVES: A commercially available portable metabolic measurement system, based on breath-to-breath gas analysis and flow spirometry, was adapted to the horse's physiology and morphology (Cosmed K4b2 and Equimask) and its validity tested by (1) repeatability of the measures and (2) comparing metabolic data to those obtained by a reference method (RM). METHODS: To test the reproducibility of the measurements, 5 healthy saddle horses were subjected twice at 2 day intervals to a similar submaximal standardised incremental exercise test on a treadmill. The same horses performed twice at one week interval an incremental treadmill test to fatigue: the oxygen consumption and ventilation were measured once with the K4b2 system and once with the RM. The metabolic and ventilatory data obtained with both systems were compared. RESULTS: There was a good reproducibility of the metabolic measurements obtained by the K4b2 system at any workload. The VO2 obtained by both systems at any workload was not significantly different. However, the K4b2 expired fraction in CO2 (FETCO2) and carbon dioxide production (VCO2) were significantly lower at high and at maximal workloads. As a consequence, the values of the respiratory exchange ratio were too low and incompatible with normal physiological values. CONCLUSIONS: The good reproducibility of the metabolic and ventilatory measurements and the fact that the VO2 measurements at any workload were similar to the data obtained with the reference method suggested that this system may be used for comparison of repeated VO2 measurements in practical field conditions. POTENTIAL RELEVANCE: The K4b2 system could be used to improve knowledge of the energetic cost in different equine sports disciplines and offer the opportunity to undertake performance tests with genuine track conditions, on ridden or harnessed horses, rather than under laboratory conditions.