We report that, while old mice (18C22 months) contain fewer CD4+ T-cells compared with adults (8C12 weeks), those that remain have a higher intrinsic affinity for self-pMHC, as measured by CD5 expression. a consequence of higher affinity T-cell receptor interactions with self-pMHC. DOI: http://dx.doi.org/10.7554/eLife.05949.001 Research organism: mouse eLife digest The immune system’s T cells help the body to recognize and destroy harmful pathogens, such as viruses and bacteria. T cells remember immunity-inducing fragments, called antigens, from the pathogens they have encountered. This memory Pllp then allows the immune system to quickly fend off infections if those pathogens, or even related pathogens, invade again. Vaccines exploit the ability to form immunological memory by exposing the body to harmless forms of the pathogen, or even just particular antigens from it. This allows the T cells to learn how to identify the pathogen without any risk of illness. Vaccines have been extremely successful and have helped to virtually get rid of some diseases. However, for reasons that are unclear, the immune systems of older adults become less functional, so vaccines often shed their performance. Paradoxically, as people age T cells become more likely to assault the body’s cells, causing autoimmune diseases like arthritis. Understanding what happens to ageing T cells to cause these immune changes may help scientists design vaccines that remain effective as people age. Little is known about what happens to a particular type of T cellthe CD4+ T cellsas people age, even though this population plays a critical part in providing additional immune cells with detailed instructions on when and how to battle a pathogen. Right now, Deshpande et al. display that CD4+ T cells undergo a remarkable set of changes in ageing mice. Mice that are nearing the end of their natural life-span possess fewer CD4+ T cells than more youthful mice. However, those CD4+ T cells that remain are more likely than CD4+ T cells from more youthful mice to be able to identify multiple antigens. This increase in the proportion of multitasking CD4+ T cells corresponds with an increased tendency of these cells to bind to the body’s personal cells. If related changes occur in older people, this may help clarify some age-related autoimmune diseases. Yet, the relationship between increase in multitasking CD4+ T cells and the decrease in immune function with ageing remains to be fully explored. The challenge for scientists now is to determine how these age-related changes in CD4+ T cells impact immune reactions to vaccines or pathogens in older individuals. One implication of this work is definitely that CD4+ T cell reactions may be too powerful and out of balance with other arms of the immune system. This could actually lead to conditions such as autoimmunity. Alternatively, while there may be more CD4+ T Mianserin hydrochloride cells that can multitask by realizing multiple antigens, their ability to respond appropriately to infections or vaccinations may be diminished. What is obvious from the work of Deshpande et al. is definitely that the rules that have been defined for immunity in adults switch with aging. The rules that govern immunity in the elderly must be more clearly defined to realize the goal of developing immunotherapies, such as vaccines, that provide protection throughout the life-span. DOI: http://dx.doi.org/10.7554/eLife.05949.002 Intro Each T-cell expresses a T-cell receptor (TCR) encoded by rearranged gene segments and non-germline nucleotides. Estimations of TCR diversity Mianserin hydrochloride imply a repertoire that can bind a universe of self and foreign peptides inlayed within self-major histocompatibility complex molecules (pMHC) (Davis and Bjorkman, Mianserin hydrochloride 1988). Yet, this potential cannot be recognized. Thymic development limits clonal representation to T-cells bearing TCRs within an affinity windowpane for self-pMHC (Savage and Davis, 2001; Yin et al., 2012; Klein et al., 2014), while peripheral space literally constrains the number of T-cells present to recognize foreign-pMHC (Mason, 1998; Vrisekoop et al., 2014). Finally, timewith its age-associated changes in thymic manifestation of tissue-restricted antigens (TRAs), thymic architecture, antigen encounter, and homeostasisimposes an overarching pressure that limits the binding capacity of a repertoire for self- and foreign-pMHC to each constituent’s prior history of TCRCpMHC relationships (Nikolich-Zugich, 2008; Surh and Sprent, 2008; Chinn et al., 2012; Griffith et al., 2012). How these pressures shape the capacity of the CD4+ T-cell compartment to bind pMHC on the life-span remains mainly unexplored. Aging is definitely associated with improved susceptibility to infections and decreased responsiveness to vaccines, suggesting that individual repertoires converge on a point where their diversity is definitely insufficient to bind and/or mount a protecting.